WO2014068171A1 - N-substituted 4-aminophenols and corresponding quinone imines - Google Patents

N-substituted 4-aminophenols and corresponding quinone imines Download PDF

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Publication number
WO2014068171A1
WO2014068171A1 PCT/FI2013/000042 FI2013000042W WO2014068171A1 WO 2014068171 A1 WO2014068171 A1 WO 2014068171A1 FI 2013000042 W FI2013000042 W FI 2013000042W WO 2014068171 A1 WO2014068171 A1 WO 2014068171A1
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alkoxy
alkyl
alkylamino
compound according
hydroxy
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PCT/FI2013/000042
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French (fr)
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Gundars GOLDSTEINS
Jari Koistinaho
Milla Koistinaho
Jari Ratilainen
Jarmo Pystynen
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Medeia Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms

Definitions

  • the present disclosure relates to pharmacologically active N-substituted 4-aminophenols and corresponding quinone imines, or pharmaceutically acceptable salts, amides, and esters thereof, as well as to pharmaceutical compositions containing them and to their use as inhibitors of cytochrome c (CytC) derived peroxidase.
  • CytC cytochrome c
  • Neurodegenerative disorders are a varied assortment of nervous system disorders characterized by gradual and progressive degeneration of neural tissue and nerve cells in the brain, spinal cord, and the peripheral nervous system.
  • Chronic neurodegenerative disorders include Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, retinal degeneration, deficits in hearing and balance due to degeneration of vestibular and cochlear cells, alcoholism-related neurodegeneration, epilepsy, Alzheimer's disease and other forms of dementia including tauopathies, such as frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, and corticobasal degeneration.
  • Prion diseases, vascular dementia, HTV-associated dementia, and dementia with Lewy bodies are also disorders characterized by progressive loss of neural cells.
  • Acute types of neurodegenerative disorders are caused either by a sudden trauma to the head or spinal cord, or blockade of blood flow into the brain or other area of the nervous tissue leading to the degeneration of neurons in the affected regions. Acute
  • neurodegenerative disorders include diseases associated with an accident such as traumatic brain injury or spinal cord injury and ischemic disorders of vascular origin such as ischemic and hemorrhagic stroke, neonatal hypoxia-ischemia, and brain ischemia during coronary artery bypass grafting as well as neurodegeneration leading to neuropathy caused by viral infection such as infection caused by Herpes zoster or toxic compounds such as cytotoxic compounds used in cancer treatments.
  • ischemic disorders of vascular origin such as ischemic and hemorrhagic stroke, neonatal hypoxia-ischemia, and brain ischemia during coronary artery bypass grafting
  • neurodegeneration leading to neuropathy caused by viral infection such as infection caused by Herpes zoster or toxic compounds such as cytotoxic compounds used in cancer treatments.
  • Normal brain aging is also associated with loss of normal neuronal function and may entail the death of certain neurons.
  • Neurodegenerative disorders have a major socio-economic impact on the society. Most of these illnesses manifest themselves later in life. Therefore, as the life-
  • AD Alzheimer's disease
  • memory loss decline in the ability to perform routine tasks, disorientation, difficulty in learning, loss of language skills, impairment of judgment, and personality changes.
  • people with AD become unable to care for themselves.
  • the loss of brain cells eventually leads to the failure of other systems in the body.
  • Beta-amyloid plaques and neurofibrillary tangles in the brain are the histological hallmarks of the disease.
  • the histopathological features observed in the different forms of AD are strikingly similar, although the disease is etiologically heterogeneous.
  • Cholinesterase inhibitors prevent the breakdown of acetylcholine, which is a brain chemical involved in learning and memory.
  • Another drug, memantine works by regulating the activity of glutamate, another cell-to-cell
  • Vitamin E is sometimes prescribed because it may reduce oxidative stress contributing to brain cell damage. However, vitamin E has not been shown to have any significant effect on disease progression or symptoms. Other medications may be prescribed to treat such symptoms as agitation, anxiety, depression, and poor sleep.
  • Other strategies for treating AD have been proposed, and they include decreasing or preventing the release of beta-amyloid peptide by modulating its generation by enzymes called secretases. Other strategies include immunological control of beta-amyloid levels. However, this approach has been shown to have severe side effects such as brain hemorrhages and encephalopathy. Progressive supranuclear palsy is a rapidly progressing degenerative disease belonging to the family of tauopathies, characterized by the involvement of both cortical and subcortical structures.
  • FTD frontotemporal dementia
  • corticobasal degeneration The primary cause of the disease is unknown and disease-modifying drugs are not yet available.
  • the other two most common tauopathies are frontotemporal dementia (FTD) and corticobasal degeneration.
  • FTD is caused by neurodegeneration in the frontal and/or temporal lobes, and it exists in sporadic and familial forms. The affected neurons often display tau-protein positive aggregations. Approximately 25-40 % of FTD cases are familial.
  • Fronto temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the gene which encodes the microtubule-associated protein tau. There exists no treatment for FTDP-17.
  • Prion diseases are a heterogeneous group of histopathologial and clinical phenotypes.
  • Prion diseases can be familial such as familial Creutzfeld-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome; sporadic, such as Creutzfeld-Jakob disease and sporadic fatal insomnia; or acquired, such as kuru and variant Creutzfeld-Jakob disease.
  • the common features of these diseases include rapidly progressing neurodegeneration with spongiosis and amyloid plaques consisting of prion protein. There is no treatment available that would halt the progression of these diseases.
  • vascular dementia is not a single disease but rather a group of syndromes of different vascular origin. Many subtypes of vascular dementia have been described. The spectrum includes mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, and mixed dementia (combination of AD and vascular dementia).
  • HIV-associated dementia can occur in the absence of direct infection of neurons.
  • the major mechanisms of neurodegeneration in HlV-associated dementia involve the induction of excitotoxicity and oxidative stress.
  • Lewy body dementia has been proposed to be the second most common type of degenerative dementia and accounts for approximately 15 % of all dementia cases.
  • the histopathological feature of LBD is the presence of Lewy bodies in cortical and subcortical regions of the brain. LBD results in the atrophy of cerebral structures.
  • Parkinson's disease PD is a progressive neurological disorder marked by tremor, muscle rigidity, and balance and coordination problems. The destruction of dopaminergic neurons underlies these symptoms. The degenerating dopamine-producing neurons are also associated with protein deposits called Lewy bodies.
  • patients with PD are treated with drugs that either increase dopamine concentrations or reduce acetylcholine
  • MS Multiple sclerosis
  • CNS central nervous system
  • MS is associated with the infiltration of inflammatory cells into the brain and spinal cord, which may be the primary event in the de-myelination process or secondary to axonal damage. Ultimately, the disease leads to the degeneration of nerve cells.
  • the pathophysiology of MS is not completely understood.
  • the symptoms of MS vary depending on the location of the affected nerve axons. The symptoms include numbness, weakness or paralysis of one or more limbs, brief pain or electric shock sensations, tremor, lack of coordination, fatigue, and dizziness. As the disease progresses, muscle spasms, slurred speech, vision problems, and sexual problems may arise.
  • the existing disease-modifying therapies for MS are only partially effective and include interferon beta-la and -lb preparations, glatiramer acetate, mitoxantrone, and fingolimod.
  • ALS Amyotrophic lateral sclerosis
  • Lou Gehrig's disease is a rapidly progressing, invariably fatal neurological disease that attacks the neurons responsible for controlling voluntary muscles.
  • the disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons.
  • Motor neurons are nerve cells located in the brain, brainstem, and spinal cord that serve as controlling units and vital communication links between the nervous system and the voluntary muscles of the body.
  • Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of ALS symptoms.
  • ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die when they are exposed over long periods to excessive amounts of glutamate.
  • HD is one of a number of late-onset neurodegenerative disorders caused by expanded glutamine repeats, with a likely similar biochemical basis. Immunohistochemical studies have identified neuronal inclusions within densely stained neuronal nuclei, peri-nuclear, and within dystrophic neuritic processes. In the absence of effective therapy, treatment of HD aims at slowing progression and maximizing the ability to function for as long as possible. Medications vary depending on the symptoms.
  • Epilepsy is a common, chronic neurological disorder characterized by recurrent unprovoked seizures. Experimental modeling and clinical neuroimaging of patients have shown that certain seizures are capable of causing neuronal death and long term behavioral and cognitive disturbances. The current treatment of epilepsy focuses on the prevention or suppression of seizures.
  • Chronic alcoholism is a progressive neurodegenerative disease.
  • Neuroradiological studies have demonstrated that the brains of chronic alcoholics undergo loss of both gray and white matter.
  • Neuropathological studies have demonstrated the loss of neurons in specific parts of the brain in chronic alcoholics.
  • specific alterations occur in the function and morphology of the diencephalon, medial temporal lobe structures, basal forebrain, frontal cortex, and cerebellum, while other subcortical structures, such as the caudate nucleus, seem to be relatively spared.
  • Glaucoma is a common problem of the aging eye. Glaucoma causes elevation of the pressure within the eye. The pressure within the vitreous chamber increases and
  • Retinitis pigmentosa is a severe hereditary disease of the retina for which there is no cure available.
  • the rod cells of the peripheral retina begin to degenerate in early stages of the disease. Patients gradually become night blind as more and more of the peripheral retina becomes damaged. Eventually the vision is reduced to tunnel vision with only the fovea spared.
  • the complex architecture of the inner ear houses the senses of both balance and hearing.
  • the hair cells and neurons are the most vulnerable cells of the cochlea, and the degeneration of these cells is the most common cause of permanent hearing loss.
  • Cochlear neurons may be damaged due to swelling of the spiral ganglion dendrites caused by intense noise and ischemia or secondary to the degeneration of hair cells.
  • Cerebrovascular accident is a clinical definition used to describe symptoms of an acute neurological disorder caused by disturbance of the cerebral blood supply. 80 % of CVAs are of ischemic type. Focal (regional) ischemia is clinically more common than global (forebrain) ischemia. The major causes of cerebral infarction are vascular thrombosis, cerebral embolism, hypotension, hypertensive hemorrhage, and anoxia/hypoxia.
  • hypoxic-ischemic disturbances are most often caused by hypoperfusion, because the arterial partial pressure of oxygen is low. Severe hypoxia can occur leading to myocardial dysfunction with subsequent cerebral hypoperfusion or loss of cerebrovascular autoregulation. This cerebral hypoperfusion in turn may lead to neuronal ischemia.
  • In utero hypoxia is usually the result of placental insufficiency. Infants who have experienced in utero hypoxia often have clinically significant respiratory or cardiac failure after birth. As a comparison, postnatal hypoxia is the result of either respiratory or cardiac insufficiency, alone or in combination. Anesthesia and surgery carry a high risk of cerebrovascular complications such as ischemia.
  • Reperfusion injury occurs when blood flow is restored to the affected area after an ischemic period of more than 10 minutes. For example, as many as 80 % of patients undergoing coronary artery bypass grafting (CABG) display some cognitive impairment after surgery which persists in 25 % of these people still at six months after surgery.
  • CABG coronary artery bypass grafting
  • acute neurodegeneration may be induced by physical trauma to the head or spinal cord (traumatic brain injury and spinal cord injury, respectively).
  • the neuronal cell loss that is associated with such disorders may be due to necrosis or apoptosis.
  • neurodegenerative diseases Despite the etiologically heterogeneous background of neurodegenerative diseases, cell death in neurodegenerative diseases appears to involve similar pathways. Neurodegenerative diseases exhibit signs of oxidative stress, inflammation, mitochondrial injury, and apoptosis. Thus rational therapeutic strategies that prevent or stop further cellular death due to upstream interference with signaling cascade leading to mitochondrial injury and apoptosis could be useful in the treatment of a number of neurodegenerative diseases.
  • One such strategy is to prevent the harmful downstream effects of CytC, assuming peroxidase activity during the early steps of a cascade leading to apoptotic cell death.
  • CytC functions as a shuttle within mitochondrial electron transport chain.
  • the heme group of CytC accepts electrons from Complex ⁇ and transfers them to Complex IV.
  • CytC is also involved in the initiation of apoptosis, and release of CytC from mitochondria to cytoplasm is a well-documented feature of apoptotic cell death. More detailed studies on molecular mechanisms preceding CytC release from mitochondria (for example, Kagan, V. E. et al. Mol. Nutr. Food Res., 53 (2009) 104) have revealed that CytC acts as a cardiolipin- specific peroxidase.
  • Peroxidation products of activated CytC are essential for mitochondrial membrane permeabilization and release of pro-apoptotic factors into the cytosol.
  • the peroxidation reaction of CytC/cardiolipin complex is fuelled by hydrogen peroxide, which acts as a source of oxidizing equivalents.
  • N-substituted 4-aminophenols and corresponding quinone imines possess CytC derived peroxidase inhibiting activity, act as potent molecules preventing cell death in vitro, suppress production of inflammatory mediators, and result in cytoprotection in vivo.
  • An object of the present disclosure is to provide inhibitors of cytochrome c derived peroxidase that can be used for the treatment of neurodegenerative disorders. Accordingly, an object of the present disclosure is to provide compounds to be used as CytC derived peroxidase inhibiting agents in the treatment of mammals, including humans. Furthermore, pharmaceutical compositions containing the present compounds are provided.
  • CytC derived peroxidase inhibiting agents of the present disclosure possess enhanced primary pharmacological properties, that is CytC derived peroxidase inhibiting activity. Additionally, the compounds are not pro-oxidative, and thus possess a desirable safety profile.
  • Figure 2a Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing high (0-10 ⁇ ) concentrations of the compound of Example 2.
  • Figure 2b Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing low (0-80 nM) concentrations of the compound of Example 2.
  • Figure 2c Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing high (0-10 ⁇ ) concentrations of the compound of Example 7.
  • Figure 2d Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing low (0-80 nM) concentrations of the compound of Example 7.
  • Figure 3a Summary of data showing the effect of the compound of Example 2 on nitric oxide (NO) release (% of LPS control) from BV2 cells upon lipopolysaccaride (LPS) stimulation at 24 h time point in the presence of compound alone or together with 50 ng/ml LPS. The NO release from BV2 cells exposed to LPS only was normalized to 100 %.
  • NO nitric oxide
  • LPS lipopolysaccaride
  • Figure 3b Summary of data showing the effect of the compound of Example 2 on the amount of interleukin-6 (EL-6), monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor a (TNFa) in culture media of BV2 cells stimulated with LPS for 24 h.
  • EL-6 interleukin-6
  • MCP-1 monocyte chemotactic protein 1
  • TNFa tumor necrosis factor a
  • Q 1 ; Q 2 , or Q 3 are N, and one of Q 1 ; Q 2 , or Q 3 is CR 6 ;
  • R 2 is (Q-C ⁇ alkyl, halogen, hydroxy, (Ci-C 6 )alkoxy, (C]-C6)alkylthio, amino,
  • R_i is, independently at each occurrence, H, (Q-C ⁇ alkyl, halogen, hydroxy, or
  • R 5 is H or (C r C 6 )alkyl
  • R 6 is H, (C C 6 )alkyl, halogen, hydroxy, (C C 6 )alkoxy, (C 1 -C 6 )alkylthio, amino,
  • the present disclosure relates to compounds of formula ⁇ ,
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein Qi is N, Q 2 is N, and Q 3 is CR 6 .
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein Qj is N + -0 , Q 2 is N, and Q 3 is CR 6 .
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein Qi is N, Q 2 is CR 6 , and Q 3 is N + -0 .
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein Qi is N + -0 ⁇ Q 2 is CR 6 , and Q 3 is N.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein R* is, independently at each occurrence, H, (C 1 -C 6 )alkyl, halogen, or
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein R 5 is H.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein R 3 is tert-butyl.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein R 2 is halogen, hydroxy, (Ci-C 6 )alkoxy, (Q-C ⁇ alkylthio, amino,
  • halo(Q-C 6 )alkoxy In one embodiment the present disclosure relates to compounds of formula I or formula ⁇ , wherein R 2 is halogen or (Q-C ⁇ alkoxy.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein R 2 is halogen or methoxy.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein Ri is halogen or (CrC 6 )alkoxy;
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein
  • Ri is halogen, hydroxy, (CrC 6 )alkoxy, (C]-C 6 )alkylthio, amino, (Ci-C 6 )alkylamino, di(Ci-C 6 )alkylamino, heterocyclyl, halo(CrC 6 )alkyl, hydroxy(Ci-C )alkyl, or
  • R 3 is tert-butyl or l-hydroxy-2-methylprop-2-yl
  • R 4 is, independently at each occurrence, H, (C 1 -C 6 )alkyl, halogen, or (Ci-C 6 )alkoxy;
  • R 5 is H or (C r C 6 )alkyl
  • Qi is N
  • Q 2 is N
  • Q 3 is CR 6 ;
  • Qi is N
  • Q 2 is CR 6
  • Q 3 is N
  • Ri is halogen, hydroxy, (CrC6)alkoxy, (CrC 6 )alkylthio, (CrC 6 )alkylamino,
  • R 2 is halogen, hydroxy, (C r C 6 )alkoxy, (CrC 6 )alkylthio, amino, (Ci-C 6 )alkylamino, di(C 1 -C6)alkylamino, morpholino, halo(CrC 6 )alkyl, or halo(C ! -C 6 )alkoxy;
  • R 3 is tert-butyl or l-hydroxy-2-methylprop-2-yl
  • R 4 is, independently at each occurrence, H, methyl, halogen, or methoxy
  • R 6 is H, halogen, or methoxy.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein
  • Qi is N
  • Q 2 is N
  • Q 3 is CR 6 ;
  • Qi is N
  • Q 2 is CR 6
  • Q 3 is N
  • Ri is halogen or (Q-C ⁇ alkoxy
  • R 2 is halogen or (CrC 6 )alkoxy
  • R 5 is H
  • R 6 is H.
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein
  • Qi is N
  • Q 2 is N
  • Q 3 is CR 6 ;
  • Qi is N
  • Q 2 is CR 6
  • Q 3 is N
  • R 5 is H
  • the present disclosure relates to compounds of formula I or formula ⁇ , wherein the compound is 4-[(5-bromo-3-methoxypyrazin-2-yl)imino]-2,6-di-tert- butylcyclohexa-2,5-dien- 1 -one, 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert- butylphenol, 2,6-di-tert-butyl-4-[(2-chloro-4-methoxypyrimidin-5-yl)amino]phenol, 2,6-di- tert-butyl-4-[(2,4-dichloropyrimidin-5-yl)amino]phenol, 2,6-di-tert-butyl-4-[(3,5- dimethoxypyrazin-2-yl)amino]phenol, 2,6-di-tert-butyl-4-[(2,4-dimeth
  • (C 1 -C 6 )alkyl refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atom(s).
  • Representative examples of (CrC 6 )alkyl include, but are not limited to, methyl, ethyl, and tert-butyl.
  • halo or “halogen”, as employed herein as such or as part of another group, refers to fluorine, chlorine, bromine, or iodine.
  • hydroxy refers to a -OH group.
  • (C 1 -C 6 )alkoxy refers to an (C 1 -C 6 )alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of (Ci-C 6 )alkoxy include, but are not limited to, methoxy, isopropoxy, and tert-butoxy.
  • amino refers to a -N3 ⁇ 4 group.
  • (C]-C 6 )alkylamino refers to an (Cj-C 6 )alkyl group, as defined herein, appended to the parent molecular moiety through a -NH- group.
  • Representative examples of (C 1 -C 6 )alkylamino include, but are not limited to, methylamino, butylamino, and tert-butylamino.
  • diiCrC ⁇ alkylamino as employed herein as such or as part of another group, refers to two (Ci-C 6 )alkyl groups, as defined herein, both appended to the parent molecular moiety through the same nitrogen atom.
  • the (CrC 6 )alkyl groups can be identical or different.
  • Representative examples of di(C 1 -C 6 )alkylamino include, but are not limited to, dimethylamino, diethylamino, and isopropylmethylamino.
  • N-(C 1 -C6)alkyl-N-(C 2 -C 7 )alkanoylamino refers to an (Ci-C 6 )alkyl group, as defined herein, and an (C 2 -C 7 )alkanoyl group, as defined herein, both appended to the parent molecular moiety through the same nitrogen atom.
  • heterocyclyl refers to an unsubstituted 5- or 6-membered saturated monocyclic group containing 1 or 2 ring heteroatom(s) each independently selected from N, O, and S.
  • Representative examples of heterocyclyl include, but are not limited to, pyrrolidin-l-yl, piperidin-l-yl, and morpholino.
  • halo(CrC 6 )alkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an (C]-C 6 )alkyl group, as defined herein.
  • the halogens can be identical or different and each halogen can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.
  • Representative examples of halo(C 1 -C 6 )alkyl include, but are not limited to, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.
  • hydroxyCd-C ⁇ alkyl refers to one or two hydroxy group(s), as defined herein, appended to the parent molecular moiety through an (Q-C 6 )alkyl group, as defined herein. When there are two hydroxy groups, both hydroxy groups can be attached to the same carbon atom or the hydroxy groups can be attached to different carbon atoms.
  • Representative examples of hydroxy Q-Ce ⁇ lkyl include, but are not limited to,
  • (C 1 -C 6 )alkoxy(C 1 -C6)alkyl refers to one or two
  • the (CrC 6 )alkoxy groups can be identical or different and both (CrC 6 )alkoxy groups can be attached to the same carbon atom or the (Q-C ⁇ alkoxy groups can be attached to different carbon atoms.
  • Representative examples of (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl include, but are not limited to, methoxymethyl, 1-methoxyethyl, and tert-butoxymethyl.
  • the (Cj-C 6 )alkylthio groups can be identical or different and both (C 1 -C 6 )alkylthio groups can be attached to the same carbon atom or the (CrC 6 )alkylthio groups can be attached to different carbon atoms.
  • Representative examples of (C 1 -C 6 )alkylthio(Ci-C6)alkyl include, but are not limited to, methylthiomethyl, l-(ethylthio)ethyl, and
  • amino(CrC 6 )alkyl refers to a -NH 2 group appended to the parent molecular moiety through an (CrC6)alkyl group, as defined herein.
  • Representative examples of amino(Ci-C 6 )alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, and 1-aminobutyl.
  • ((C 1 -C 6 )alkylamino)(C 1 -C 6 )alkyl refers to an
  • ((C 1 -C 6 )alkylamino)(C 1 -C 6 )alkyl include, but are not limited to, methylaminomethyl, l-(methylamino)ethyl, and 3-(methylamino)propyl.
  • (di(C 1 -C 6 )alkylamino)(C 1 -C 6 )alkyl include, but are not limited to, dimethylaminomethyl, 3-(dimethylamino)propyl, and l-(isopropylmethylamino)ethyl.
  • ((C 2 -C 7 )alkanoylamino)(CrC 6 )alkyl include, but are not limited to, acetylaminomethyl, l-(propionylamino)efhyl, and 3-(propionylamino)propyl.
  • (N-(C 1 -C 6 )alkyl-N-(C 2 -C 7 )alkanoylamino)(Ci-C 6 )alkyl refers to a N-(C]-C 6 )alkyl-/V-(C 2 -C 7 )alkanoylamino group, as defined herein, appended to the parent molecular moiety through an (Ci-C 6 )alkyl group, as defined herein.
  • Representative examples of (N-(C 1 -C 6 )alkyl-N-(C 2 -C 7 )alkanoylamino)(C 1 -C 6 )alkyl include, but are not limited to, N-acetyl-N-methylaminomethyl, l-(N-methyl- N-propionylamino)ethyl, and 3-(N-acetyl-N-ethylamino)propyl.
  • halo(C 1 -C 6 )alkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an (C C6)alkoxy group, as defined herein.
  • the halogens can be identical or different and each halogen can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.
  • Representative examples of halo(C 1 -C 6 )alkoxy include, but are not limited to, trifluoromethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, and 3-chloropropoxy.
  • hydroxy(Ci-C 6 )alkoxy refers to one or two hydroxy group(s), as defined herein, appended to the parent molecular moiety through an
  • (C 1 -C 6 )alkoxy group as defined herein.
  • both hydroxy groups can be attached to the same carbon atom or the hydroxy groups can be attached to different carbon atoms.
  • Representative examples of hydroxy(C 1 -C 6 )alkoxy include, but are not limited to, hydroxymethoxy, 3-hydroxypropoxy, and 3-hydroxy-2,2-dimefhylpropoxy.
  • (Ci-C 6 )alkoxy(C 1 -C 6 )alkoxy refers to one or two
  • the (CrC 6 )alkoxy groups can be identical or different.
  • both (Q-C ⁇ alkoxy groups can be attached to the same carbon atom or the (C]-C 6 )alkoxy groups can be attached to different carbon atoms.
  • Representative examples of (Ci-C 6 )alkoxy(CrC 6 )alkoxy include, but are not limited to, methoxymethoxy, 2-methoxyethoxy, and 3-methoxy-2,2-dimethylpropoxy.
  • amino(C 1 -C 6 )alkoxy refers to a -NH 2 group appended to the parent molecular moiety through an (C r C 6 )alkoxy group, as defined herein.
  • amino(C 1 -C )alkoxy include, but are not limited to,
  • ((CrC 6 )alkylamino)(CrC 6 )alkoxy include, but are not limited to, methylaminomethoxy, 2-(ethylamino)ethoxy, and 2,2-dimethyl-3-(methylamino)propoxy.
  • (di(C 1 -C 6 )alkylamino)(Ci-C 6 )alkoxy include, but are not limited to, dimethylaminomethoxy, 2-(diethylamino)ethoxy, and 3-(ethylmethylamino)propoxy.
  • ((C 2 -C 7 )alkanoylamino)(Ci-C 6 )alkoxy include, but are not limited to, acetylaminomethoxy, acetylaminodimethylmethoxy, and 2-(butanoylamino)ethoxy.
  • (N-(C]-C 6 )alkyl-N-(C 2 -C 7 )alkanoylamino)(Ci-C 6 )alkoxy refers to a N-(C 1 -C 6 )alkyl-N-(C 2 -C 7 )alkanoylamino group, as defined herein, appended to the parent molecular moiety through an (C 1 -C )alkoxy group, as defined herein.
  • heterocyclyl(CrC 6 )alkoxy refers to a heterocyclyl group, as defined herein, appended to the parent molecular moiety through an (Q-C ⁇ alkoxy group, as defined herein.
  • Representative examples of heterocyclyl(C 1 -C 6 )alkoxy include, but are not limited to, morpholinomethyl, 2-piperidin-l-ylethyl, and 3-pyrrolidin- l-ylpropyl.
  • Representative examples of (Cj-C 6 )alkylsulfinyl include, but are not limited to, methylsulfinyl, isopropylsulfinyl, and neopentylsulfinyl.
  • Representative examples of (Cj-C 6 )alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and isobutylsulfonyl.
  • (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkoxy refers to an
  • (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkoxy include, but are not limited to, methylsulfinylmethoxy, 2-(isopropylsulfinyl)ethoxy, and 2,2-dimethyl-3-(methylsulfinyl)propoxy.
  • hydrosulfonyl(CrC 6 )alkoxy refers to a hydrosulfonyl group, as defined herein, appended to the parent molecular moiety through an (Ci-C 6 )alkoxy group, as defined herein.
  • Representative examples of hydrosulfonyl(C 1 -C 6 )alkoxy include, but are not limited to, hydrosulfonylmethoxy, 3-hydrosulfonylpropoxy, and
  • (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkoxy refers to an
  • (C]-C 6 )alkylsulfonyl(CrC 6 )alkoxy include, but are not limited to, methylsulfonylmethoxy, 2-(isopropylsulfonyl)ethoxy, and 2,2-dimethyl-3-(methylsulfonyl)propoxy.
  • esters of hydroxy groups may be prepared by known methods using pharmaceutically acceptable carboxylic acids that are conventional in the field of pharmaceuticals.
  • Representative examples of pharmaceutically acceptable esters of hydroxy groups include, but are not limited to, esters formed with acetic acid, propionic acid, butyric acid, and pentanoic acid.
  • the present disclosure includes within its scope all the possible geometric isomers, such as Z and E isomers (cis and trans isomers), of the compounds as well as all the possible optical isomers, such as diastereomers and enantiomers, of the compounds. Furthermore, the present disclosure includes in its scope both the individual isomers and any mixtures thereof, such as racemic mixtures.
  • the individual isomers may be obtained using the corresponding isomeric forms of the starting material, or they may be separated after the preparation of the end compound according to conventional separation methods.
  • optical isomers such as enantiomers
  • conventional resolution methods such as fractional crystallization
  • the compounds of formula I or formula ⁇ can be prepared by a variety of synthetic routes analogously to or according to methods known in the literature using suitable starting materials. Some methods useful for the preparation of the compounds of formula I or formula ⁇ are described below.
  • (C r C 6 )alkyl (C r C 6 )alkyl.
  • Compound la is alkylated with an (C]-C 6 )alkyl halide, such as (CrC 6 )alkyl iodide, (C!-C 6 )alkyl bromide or (C]-C 6 )alkyl chloride, in the presence of a base.
  • an (C]-C 6 )alkyl halide such as (CrC 6 )alkyl iodide, (C!-C 6 )alkyl bromide or (C]-C 6 )alkyl chloride
  • Any starting material or intermediate in the reactions to prepare compounds according to the present disclosure can be protected, if necessary, in a manner well known in the chemical field. Any protected functionality can subsequently be deprotected in a manner known in the art.
  • A1C1 3 (651 mg, 4.9 mmol) was added to a solution of pyridine (0.95 ml) and 1,2- dichloroethane (25 ml). The resulting mixture was refluxed for 15 min. 2,6-Di-tert-butyl- 1,4-benzoquinone (434 mg, 1.97 mmol) and 5-bromo-3-methoxypyrazin-2-amine (420 mg, 1.97 mmol) was added and the resulting mixture was refluxed for 18 h. After cooling to RT, the mixture was filtered through celite. Celite was washed with DCM and the combined organic phase was concentrated under reduced pressure. The product was purified using column chromatography. Yield: 80 mg
  • N-Bromosuccinimide (5.1 g, 28.7 mmol) was added slowly and portion wise to a mixture of aminopyrazine (1.3 g, 13.6 mmol) in dimethylsulfoxide (11 ml) and water (17 ml). During the addition of N-bromosuccinimide, the temperature of the reaction mixture was maintained below 15 °C. After the addition, the reaction mixture was stirred for 16 h at RT. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 10 % Na 2 C0 3 solution followed by washing with water and brine. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo to obtain crude product. The product was purified using column chromatography. Yield: 1.51 g
  • 2,6-Di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)amino]phenol was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert- butylphenol in Example 2.
  • 1.37 g (10.3 mmol) of A1C1 3 , 1.99 ml of pyridine, 30 ml of 1,2- dichloroethane, 909 mg (4.12 mmol) of 2,6-di-tert-butyl-l,4-benzoquinone, and 640 mg (4.12 mmol) of 3,5-dimethoxypyrazin-2-amine was used. Yield: 250 mg
  • 2,6-Di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)imino]cyclohexa-2,5-dien-l-one was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2- yl)imino]-2,6-di-tert-butylcyclohexa-2,5-dien-l-one in Example 1.
  • the background was subtracted from the rate of CytC catalyzed peroxidation and the rate of CytC catalyzed peroxidation in the absence of a compound was set to 100 %. Data were saved in Excel format and expressed as apparent target activity at a particular compound concentration.
  • glutamate toxicity can be used as a model for oxidative stress-induced cell death in which glutamate causes glutathione depletion and oxidative stress independent of excitotoxicity (for example, Lewerenz, J. et al. J. Neurochem., 98 (2006) 916).
  • Undifferentiated PC 12 cells were plated in 96-well plates (10,000 cells/well in 100 ⁇ medium (Dulbecco's Modified Eagle Medium GlutaMAX Gibco, supplemented with 5 % fetal bovine serum (FBS; Gibco, #10270-106) and 5 % horse serum (HS; Gibco, #26050-088))). Medium was replaced 48 h after plating with 100 ⁇ serum-free medium containing various concentrations of toxin to first establish glutamate dose response. The concentration of glutamate that yielded 70-90 % cytotoxicity in vehicle treated wells was selected for screening potential cytoprotective effects of study compounds.
  • 100 ⁇ medium Dulbecco's Modified Eagle Medium GlutaMAX Gibco, supplemented with 5 % fetal bovine serum (FBS; Gibco, #10270-106) and 5 % horse serum (HS; Gibco, #26050-088)
  • Controls included cells exposed to plain medium (scaled to 100 % viability), glutamate only, or study compounds alone without glutamate to assess potential cytotoxicity of the study compounds on PC 12 cells. Six parallel wells were exposed. After 24-h incubation resazurin viability assay was performed.
  • Resazurin is a dye producing highly fluorescent resorufin when reduced by oxidoreductases within viable cells. Measurement of resazurin fluorescence is therefore an indicator of the viability of the cell. Following the glutamate exposure, medium was removed and replaced with 100 ⁇ of 10 ⁇ pre-warmed resazurin (Sigma, R7017). The working solution of resazurin was prepared from 50 mM resazurin in Hank's Buffered Salt Solution (HBSS; Lonza, BE10-547F) stock solution. The plates were incubated for 2 h at 37 °C, 5 % C0 2 .
  • HBSS Hank's Buffered Salt Solution
  • Resorufin fluorescence was measured at 530 nm / 590 nm (excitation/emission) using Victor 1420 multilabel reader. Data were saved in Excel format. The fluorescence of the blank (no cells) was subtracted from all values. Control wells which contained cells that were not exposed to glutamate were normalized to 100 %. The data were presented as a percentage of viable cells as a function of compound concentration (in the presence or absence of glutamate).
  • the Student's T-test was used to determine whether the difference between the means for two measurement groups (treatment group at selected concentration vs. vehicle treated cells) was statistically significant. P values were calculated by embedded Microsoft Excel 2007 function using two-tailed distribution and two-sample equal variance T-test.
  • LPS Bacterial lipopolysaccaride
  • NO nitric oxide
  • TNFa tumor necrosis factor a
  • MCP-1 interleukin-6
  • IL-6 interleukin-6
  • the murine microglial BV2 cell line was grown in RPMI-1640 (Sigma, R0883) medium containing 10 % heat inactivated FBS (Gibco, 10270) supplemented with L-glutamine
  • nitrite is the primary stable and nonvolatile breakdown product of NO by Griess reagent system (Promega) according to manufacturer's instructions.
  • mice 25-30 g body weight were maintained at National Laboratory Animal Center, Kuopio, Finland. The mice were housed in standard temperature
  • each subject was anesthetized with 5 % halothane for induction and 1 % for maintenance in carrier gas of 0 2 (30 %) and N 2 0 (70 %).
  • Permanent focal cerebral ischemia was produced by cauterizing the middle cerebral artery (MCA) at the level of the inferior cerebral vein.
  • MCA middle cerebral artery
  • the body temperature was maintained at 36-37 °C during the surgery with a heating pad.
  • the left temporoparietal region of the head was shaved and a midline incision was made between the orbit and ear to expose the skull.
  • the treatments with study compounds were started at 12 h prior to MCA occlusion and continued thereafter at 12 h intervals until 60 h post-occlusion.
  • the compounds were formulated in 0.5 % carboxymethylcellulose (CMC) at 9 mg/ml and administered p.o. at the dose of 30 mg/kg. Vehicle treated mice received an equal volume of CMC only.
  • CMC carboxymethylcellulose
  • mice were imaged with magnetic resonance imaging (MRI) 72 h after the lesion.
  • MRI data were acquired at 4.7 T (Magnex Scientific Ltd., Abington, United Kingdom) interfaced to a Varian UNITYINOVA console (Varian, Inc., Palo Alto, CA, United States).
  • a quadrature volume coil (Rapid Biomedical, Germany) was used for transmission and a surface coil for reception.
  • Mice anesthetized with isoflurane (1 % during imaging, carrier gas of 0 2 (30 %) and N 2 0 (70 %)) were fixed to a head holder and positioned in the magnet bore in a standard orientation relative to gradient coils.
  • TR 2 s
  • total TE 50 ms
  • matrix size of 256 x 128, FOV of 25.6 mm 2 x 25.6 mm 2 a slice thickness of 0.8 mm, 2 averages.
  • the mice were killed with C0 2 , brains quickly removed and checked for proper site of MCA occlusion.
  • the lesions were outlined manually from T2-weighted MRI images using MATLAB software.
  • the lesion volumes were calculated by Shuaib's indirect formula (Shuaib, A. et al. Stroke, 33 (2002) 3033).
  • Statistical analyses were performed and P values calculated by embedded
  • the compounds of formula I or formula ⁇ exhibit CytC derived peroxidase inhibiting activity.
  • the present disclosure thus provides compounds for use as a medicament.
  • Compounds for use in the treatment of a neurodegenerative disorder are also provided. Furthermore, a method for the treatment of a neurodegenerative disorder is provided. In said method a therapeutically effective amount of at least one compound of formula I or formula ⁇ is administered to a mammal, such as a human, in need of such treatment. Use of the compounds of formula I or formula ⁇ for the manufacture of a medicament for the treatment of a neurodegenerative disorder is also provided.
  • the aforementioned neurodegenerative disorder is Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, familial Creutzfeld- Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome,
  • Creutzfeld- Jakob disease sporadic fatal insomnia, kuru, variant Creutzfeld- Jakob disease, mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, mixed dementia (combination of Alzheimer's disease and vascular dementia), HIV-associated dementia, Lewy body dementia,
  • Parkinson's disease multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, chronic alcoholism, retinitis pigmentosa, deficit in hearing due to degeneration of vestibular and cochlear cells, deficit in balance due to degeneration of vestibular and cochlear cells, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, a neurodegenerative disease associated with neonatal hypoxia-ischemia, or a neurodegenerative disease associated with ischemia during coronary artery bypass grafting.
  • the aforementioned neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, or a neurodegenerative disease associated with neonatal hypoxia-ischemia.
  • the compounds of formula I or formula ⁇ can be administered, for example, enterally, topically or parenterally by means of any pharmaceutical formulation useful for said administration and comprising as an active ingredient at least one compound of formula I or formula ⁇ in pharmaceutically acceptable and effective amounts together with
  • the therapeutic dose to be given to a patient in need of the treatment will vary depending on the compound being administered, the age and the sex of the subject being treated, the particular condition being treated, as well as the route and method of administration, and may be determined by a person skilled in the art.
  • a typical dosage for oral administration is from 10 ng kg to 100 mg/kg per day and for parenteral administration from 1 ng/kg to 10 mg/kg for an adult mammal.
  • the compounds according to the present disclosure are given to a patient as such or in combination with one or more other active ingredients and/or suitable pharmaceutical excipients.
  • the latter group comprises conventionally used excipients and formulation aids such as fillers, binders, disintegrating agents, lubricants, solvents, gel forming agents, emulsifiers, stabilizers, colorants, and/or preservatives.
  • the compounds of formula I or formula ⁇ are formulated into dosage forms using commonly known pharmaceutical manufacturing methods.
  • the dosage forms can be, for example, tablets, capsules, granules, suppositories, emulsions, suspensions, or solutions.
  • the amount of the active ingredient in the formulation can typically vary between 0.01 % and 100 % (w/w).
  • the compounds of formula I or formula ⁇ can be given together with one or more other active ingredients, each in its own composition or two or more of the active ingredients combined in a single composition.
  • the compounds of formula I or formula II can be given together with one or more other active ingredients in the treatment of, for example, MS, ALS, or a neurodegenerative disease associated with ischemic stroke.
  • the compounds of formula I or formula ⁇ can be given together with one or more immunomodulators, such as methylprednisolone, interferon beta, natalizumab, glatiramer, fingolimod, dimethyl fumarate, or teriflunomide.
  • the compounds of formula I or formula II can be given together with riluzole.
  • the compounds of formula I or formula ⁇ can be given together with one or more thrombolytic agents, such as alteplase, or as an adjunct to thrombectomy.

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Abstract

Compounds of formula I or formula II, wherein Q1Q3 and R1-R5 are as defined in the claims, exhibit CytC derived peroxidase inhibiting activity and are thus useful as CytC derived peroxidase inhibiting agents.

Description

N-SUBSTITUTED 4-AMINOPHENOLS AND CORRESPONDING QUINONE IMINES FIELD OF THE INVENTION
The present disclosure relates to pharmacologically active N-substituted 4-aminophenols and corresponding quinone imines, or pharmaceutically acceptable salts, amides, and esters thereof, as well as to pharmaceutical compositions containing them and to their use as inhibitors of cytochrome c (CytC) derived peroxidase.
BACKGROUND OF THE INVENTION
Neurodegenerative disorders are a varied assortment of nervous system disorders characterized by gradual and progressive degeneration of neural tissue and nerve cells in the brain, spinal cord, and the peripheral nervous system. Chronic neurodegenerative disorders include Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, retinal degeneration, deficits in hearing and balance due to degeneration of vestibular and cochlear cells, alcoholism-related neurodegeneration, epilepsy, Alzheimer's disease and other forms of dementia including tauopathies, such as frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, and corticobasal degeneration. Prion diseases, vascular dementia, HTV-associated dementia, and dementia with Lewy bodies are also disorders characterized by progressive loss of neural cells. Acute types of neurodegenerative disorders are caused either by a sudden trauma to the head or spinal cord, or blockade of blood flow into the brain or other area of the nervous tissue leading to the degeneration of neurons in the affected regions. Acute
neurodegenerative disorders include diseases associated with an accident such as traumatic brain injury or spinal cord injury and ischemic disorders of vascular origin such as ischemic and hemorrhagic stroke, neonatal hypoxia-ischemia, and brain ischemia during coronary artery bypass grafting as well as neurodegeneration leading to neuropathy caused by viral infection such as infection caused by Herpes zoster or toxic compounds such as cytotoxic compounds used in cancer treatments. Normal brain aging is also associated with loss of normal neuronal function and may entail the death of certain neurons. Neurodegenerative disorders have a major socio-economic impact on the society. Most of these illnesses manifest themselves later in life. Therefore, as the life-expectancy increases, the number of people suffering from these disorders will grow. At the moment, there is no cure for any of the neurodegenerative disorders.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, decline in the ability to perform routine tasks, disorientation, difficulty in learning, loss of language skills, impairment of judgment, and personality changes. As the disease progresses, people with AD become unable to care for themselves. The loss of brain cells eventually leads to the failure of other systems in the body. Beta-amyloid plaques and neurofibrillary tangles in the brain are the histological hallmarks of the disease. The histopathological features observed in the different forms of AD are strikingly similar, although the disease is etiologically heterogeneous.
There are a number of drugs in the market which may help prevent some symptoms of AD from worsening for a limited time. Cholinesterase inhibitors prevent the breakdown of acetylcholine, which is a brain chemical involved in learning and memory. Another drug, memantine, works by regulating the activity of glutamate, another cell-to-cell
communication chemical. Vitamin E is sometimes prescribed because it may reduce oxidative stress contributing to brain cell damage. However, vitamin E has not been shown to have any significant effect on disease progression or symptoms. Other medications may be prescribed to treat such symptoms as agitation, anxiety, depression, and poor sleep. Several new strategies for treating AD have been proposed, and they include decreasing or preventing the release of beta-amyloid peptide by modulating its generation by enzymes called secretases. Other strategies include immunological control of beta-amyloid levels. However, this approach has been shown to have severe side effects such as brain hemorrhages and encephalopathy. Progressive supranuclear palsy is a rapidly progressing degenerative disease belonging to the family of tauopathies, characterized by the involvement of both cortical and subcortical structures. The primary cause of the disease is unknown and disease-modifying drugs are not yet available. The other two most common tauopathies are frontotemporal dementia (FTD) and corticobasal degeneration. FTD is caused by neurodegeneration in the frontal and/or temporal lobes, and it exists in sporadic and familial forms. The affected neurons often display tau-protein positive aggregations. Approximately 25-40 % of FTD cases are familial. Fronto temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the gene which encodes the microtubule-associated protein tau. There exists no treatment for FTDP-17.
Prion diseases are a heterogeneous group of histopathologial and clinical phenotypes. Prion diseases can be familial such as familial Creutzfeld-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome; sporadic, such as Creutzfeld-Jakob disease and sporadic fatal insomnia; or acquired, such as kuru and variant Creutzfeld-Jakob disease. The common features of these diseases include rapidly progressing neurodegeneration with spongiosis and amyloid plaques consisting of prion protein. There is no treatment available that would halt the progression of these diseases.
Vascular dementia is not a single disease but rather a group of syndromes of different vascular origin. Many subtypes of vascular dementia have been described. The spectrum includes mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, and mixed dementia (combination of AD and vascular dementia).
Approximately 60 % of HIV-infected people show some form of neurological impairment and neuropathological changes are found in 90 % of autopsied HIV-infected cases. HIV- associated dementia can occur in the absence of direct infection of neurons. The major mechanisms of neurodegeneration in HlV-associated dementia involve the induction of excitotoxicity and oxidative stress.
Lewy body dementia (LBD) has been proposed to be the second most common type of degenerative dementia and accounts for approximately 15 % of all dementia cases. The histopathological feature of LBD is the presence of Lewy bodies in cortical and subcortical regions of the brain. LBD results in the atrophy of cerebral structures. Parkinson's disease (PD) is a progressive neurological disorder marked by tremor, muscle rigidity, and balance and coordination problems. The destruction of dopaminergic neurons underlies these symptoms. The degenerating dopamine-producing neurons are also associated with protein deposits called Lewy bodies. Generally, patients with PD are treated with drugs that either increase dopamine concentrations or reduce acetylcholine
concentrations in the brain, but these drugs lose their effect with time, and have no impact on the disease progression. Multiple sclerosis (MS) is a chronic, possibly debilitating disease that affects the central nervous system (CNS). The disease is characterized by the loss of myelin sheath
surrounding the nerve axons. MS is associated with the infiltration of inflammatory cells into the brain and spinal cord, which may be the primary event in the de-myelination process or secondary to axonal damage. Ultimately, the disease leads to the degeneration of nerve cells. The pathophysiology of MS is not completely understood. The symptoms of MS vary depending on the location of the affected nerve axons. The symptoms include numbness, weakness or paralysis of one or more limbs, brief pain or electric shock sensations, tremor, lack of coordination, fatigue, and dizziness. As the disease progresses, muscle spasms, slurred speech, vision problems, and sexual problems may arise. The existing disease-modifying therapies for MS are only partially effective and include interferon beta-la and -lb preparations, glatiramer acetate, mitoxantrone, and fingolimod.
Amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig's disease, is a rapidly progressing, invariably fatal neurological disease that attacks the neurons responsible for controlling voluntary muscles. The disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons. Motor neurons are nerve cells located in the brain, brainstem, and spinal cord that serve as controlling units and vital communication links between the nervous system and the voluntary muscles of the body. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of ALS symptoms. Compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die when they are exposed over long periods to excessive amounts of glutamate. No cure has yet been found for ALS. Riluzole, which is believed to reduce damage to motor neurons by decreasing the release of glutamate, may prolong survival by months but does not reverse the degeneration of motor neurons. Huntington's disease (HD) is a progressive, autosomal, dominantly inherited
neurodegenerative disease that is characterized by involuntary movements (chorea), cognitive decline, and psychiatric manifestations. HD is one of a number of late-onset neurodegenerative disorders caused by expanded glutamine repeats, with a likely similar biochemical basis. Immunohistochemical studies have identified neuronal inclusions within densely stained neuronal nuclei, peri-nuclear, and within dystrophic neuritic processes. In the absence of effective therapy, treatment of HD aims at slowing progression and maximizing the ability to function for as long as possible. Medications vary depending on the symptoms. Epilepsy is a common, chronic neurological disorder characterized by recurrent unprovoked seizures. Experimental modeling and clinical neuroimaging of patients have shown that certain seizures are capable of causing neuronal death and long term behavioral and cognitive disturbances. The current treatment of epilepsy focuses on the prevention or suppression of seizures.
Chronic alcoholism is a progressive neurodegenerative disease. Neuroradiological studies have demonstrated that the brains of chronic alcoholics undergo loss of both gray and white matter. Neuropathological studies have demonstrated the loss of neurons in specific parts of the brain in chronic alcoholics. In animals including humans, specific alterations occur in the function and morphology of the diencephalon, medial temporal lobe structures, basal forebrain, frontal cortex, and cerebellum, while other subcortical structures, such as the caudate nucleus, seem to be relatively spared.
The human retina is a delicate organization of neurons, glia, and blood vessels. In some eye diseases, the retina becomes damaged and degenerative changes eventually lead to serious damage to the nerve cells that carry vital messages about the visual image to the brain. Glaucoma is a common problem of the aging eye. Glaucoma causes elevation of the pressure within the eye. The pressure within the vitreous chamber increases and
compromises the blood vessels of the optic nerve head and eventually the axons of the ganglion cells resulting in the degeneration of these cells.
Retinitis pigmentosa is a severe hereditary disease of the retina for which there is no cure available. The rod cells of the peripheral retina begin to degenerate in early stages of the disease. Patients gradually become night blind as more and more of the peripheral retina becomes damaged. Eventually the vision is reduced to tunnel vision with only the fovea spared.
The complex architecture of the inner ear houses the senses of both balance and hearing. The hair cells and neurons are the most vulnerable cells of the cochlea, and the degeneration of these cells is the most common cause of permanent hearing loss. Cochlear neurons may be damaged due to swelling of the spiral ganglion dendrites caused by intense noise and ischemia or secondary to the degeneration of hair cells.
Cerebrovascular accident (CVA) is a clinical definition used to describe symptoms of an acute neurological disorder caused by disturbance of the cerebral blood supply. 80 % of CVAs are of ischemic type. Focal (regional) ischemia is clinically more common than global (forebrain) ischemia. The major causes of cerebral infarction are vascular thrombosis, cerebral embolism, hypotension, hypertensive hemorrhage, and anoxia/hypoxia.
In fetal life, hypoxic-ischemic disturbances are most often caused by hypoperfusion, because the arterial partial pressure of oxygen is low. Severe hypoxia can occur leading to myocardial dysfunction with subsequent cerebral hypoperfusion or loss of cerebrovascular autoregulation. This cerebral hypoperfusion in turn may lead to neuronal ischemia. In utero hypoxia is usually the result of placental insufficiency. Infants who have experienced in utero hypoxia often have clinically significant respiratory or cardiac failure after birth. As a comparison, postnatal hypoxia is the result of either respiratory or cardiac insufficiency, alone or in combination. Anesthesia and surgery carry a high risk of cerebrovascular complications such as ischemia. Reperfusion injury occurs when blood flow is restored to the affected area after an ischemic period of more than 10 minutes. For example, as many as 80 % of patients undergoing coronary artery bypass grafting (CABG) display some cognitive impairment after surgery which persists in 25 % of these people still at six months after surgery.
In addition to CVAs, acute neurodegeneration may be induced by physical trauma to the head or spinal cord (traumatic brain injury and spinal cord injury, respectively). The neuronal cell loss that is associated with such disorders may be due to necrosis or apoptosis.
If the damages, traumas or injuries described above are not treated in a proper manner, they can lead to extensive death of nerve cells leading further to several permanent symptoms, including paralysis and other motor dysfunctions, sense disorders, mental disorders or even death of the patient.
Despite the etiologically heterogeneous background of neurodegenerative diseases, cell death in neurodegenerative diseases appears to involve similar pathways. Neurodegenerative diseases exhibit signs of oxidative stress, inflammation, mitochondrial injury, and apoptosis. Thus rational therapeutic strategies that prevent or stop further cellular death due to upstream interference with signaling cascade leading to mitochondrial injury and apoptosis could be useful in the treatment of a number of neurodegenerative diseases.
One such strategy is to prevent the harmful downstream effects of CytC, assuming peroxidase activity during the early steps of a cascade leading to apoptotic cell death.
Normally, CytC functions as a shuttle within mitochondrial electron transport chain. The heme group of CytC accepts electrons from Complex ΙΠ and transfers them to Complex IV. CytC is also involved in the initiation of apoptosis, and release of CytC from mitochondria to cytoplasm is a well-documented feature of apoptotic cell death. More detailed studies on molecular mechanisms preceding CytC release from mitochondria (for example, Kagan, V. E. et al. Mol. Nutr. Food Res., 53 (2009) 104) have revealed that CytC acts as a cardiolipin- specific peroxidase. Peroxidation products of activated CytC are essential for mitochondrial membrane permeabilization and release of pro-apoptotic factors into the cytosol. The peroxidation reaction of CytC/cardiolipin complex is fuelled by hydrogen peroxide, which acts as a source of oxidizing equivalents.
SUMMARY OF THE INVENTION
It has surprisingly been found that N-substituted 4-aminophenols and corresponding quinone imines possess CytC derived peroxidase inhibiting activity, act as potent molecules preventing cell death in vitro, suppress production of inflammatory mediators, and result in cytoprotection in vivo.
An object of the present disclosure is to provide inhibitors of cytochrome c derived peroxidase that can be used for the treatment of neurodegenerative disorders. Accordingly, an object of the present disclosure is to provide compounds to be used as CytC derived peroxidase inhibiting agents in the treatment of mammals, including humans. Furthermore, pharmaceutical compositions containing the present compounds are provided.
The CytC derived peroxidase inhibiting agents of the present disclosure possess enhanced primary pharmacological properties, that is CytC derived peroxidase inhibiting activity. Additionally, the compounds are not pro-oxidative, and thus possess a desirable safety profile.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : Summary of data showing normalized target activity (CytC derived peroxidase activity in the absence of a compound = 100 %) versus compound concentration.
Figure 2a: Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing high (0-10 μΜ) concentrations of the compound of Example 2.
Figure 2b: Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing low (0-80 nM) concentrations of the compound of Example 2. Figure 2c: Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing high (0-10 μΜ) concentrations of the compound of Example 7.
Figure 2d: Summary of data showing the percentage of viable cells upon glutamate (glu) induced oxidative cell death in undifferentiated PC 12 cells incubated in the presence of increasing low (0-80 nM) concentrations of the compound of Example 7. Figure 3a: Summary of data showing the effect of the compound of Example 2 on nitric oxide (NO) release (% of LPS control) from BV2 cells upon lipopolysaccaride (LPS) stimulation at 24 h time point in the presence of compound alone or together with 50 ng/ml LPS. The NO release from BV2 cells exposed to LPS only was normalized to 100 %. Figure 3b: Summary of data showing the effect of the compound of Example 2 on the amount of interleukin-6 (EL-6), monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor a (TNFa) in culture media of BV2 cells stimulated with LPS for 24 h.
Figure 4: The ischemic lesion sizes of mice treated with the compound of Example 2 and vehicle treated mice. n=14 (compound of Example 2) and n=12 (vehicle). Data are presented as average ± SD. **p<0.01
DETAILED DESCRIPTION OF THE INVENTION The present disclosure relates to compounds of formula I or formula Π,
Figure imgf000011_0001
Figure imgf000012_0001
wherein
two of Q], Q2, or Q3 are N, and one of Q1 ; Q2, or Q3 is CR6;
or one of Qi, Q2, or Q3 is N, one of Qi, Q2, or Q3 is N+-0", and one of Qi, Q2, or Q3 is CR6 Ri is (CrC6)alkyl, halogen, hydroxy, (C1-C6)alkoxy, (Q-C^alkylthio, amino,
(Ci-C6)alkylamino, diCQ-C^alkylarnino, (C2-C7)alkanoylamino, N-(C1-C6)alkyl- N-(C2-C7)alkanoylamino, heterocyclyl, halo(C]-C6)alkyl, hydroxy(CrC6)alkyl,
(Ci-C6)alkoxy(C]-C6)alkyl, (C C6)alkylthio(C C6)alkyl, amino(C1-C6)alkyl,
((C C6)alkylamino)(C1-C6)alkyl, (di(C1-C6)alkylamino)(C1-C6)alkyl,
((C2-C7)alkanoylaraino)(C 1 -C6)alkyl, (N-(C 1 -C6)alkyl-
N-(C2-C7)alkanoylamino)(Ci-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(CrC6)alkoxy,
(Ci-C6)alkoxy(CrC6)alkoxy, amino(C]-C6)alkoxy, ((CrC6)alkylamino)(Ci-C6)alkoxy,
(di(C -C6)alkylamino)(C \ -C6)alkoxy, ((C2-C7)alkanoylamino)(C \ -C6)alkoxy,
(N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino)(Ci-C6)alkoxy, heterocyclyl(C1-C6)alkoxy,
(Cj-C6)alkylsulfinyl, hydrosulfonyl, (CrC6)alkylsulfonyl,
(C 1 -C6)alkylsulfinyl(C1 -C6)alkoxy, hydrosulf onyl(C 1 -C6)alkoxy, or
(C 1 -C6)alkylsulfonyl(C 1 -C6)alkoxy ;
R2 is (Q-C^alkyl, halogen, hydroxy, (Ci-C6)alkoxy, (C]-C6)alkylthio, amino,
(Ci-C6)alkylamino, di(CrC6)alkylamino, (C2-C7)alkanoylamino, N-(CrC6)alkyl- N-(C2-C7)alkanoylamino, heterocyclyl, halo(CrC6)alkyl, hydroxy(C1-C6)alkyl,
(C1-C6)alkoxy(C1-C6)alkyl, (CrC6)alkylthio(CrC6)alkyl, amino(C C6)alkyl,
((C1-C6)alkylamino)(C1-C6)alkyl, (di(Ci-C6)alkylamino)(C1-C6)alkyl,
((C2-C7)alkanoylamino)(C]-C6)alkyl, (N-(C C6)alkyl-
N-(C2-C7)alkanoylamino)(CrC6)alkyl, halo Q-C^alkoxy, hydroxy(Ci-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)alkoxy, amino(C]-C6)alkoxy, ((Ci-C6)alkylamino)(C1-C6)alkoxy, (di(C1-C6)alkylamino)(C1-C6)alkoxy, ((C2-C7)alkanoylamino)(Ci-C6)alkoxy,
(N-(C i -C6)alkyl-N-(C2-C7)alkanoylamino)(C 1 -C6)alkoxy, heterocyclyl(C 1 -C6)alkoxy , (Ci-C6)alkylsulfinyl, hydrosulfonyl, (C1-C6)alkylsulfonyl,
(Ct-C6)alkylsulfinyl(Ci-C6)alkoxy, hydrosulfonyl(Ci-C6)alkoxy, or (C i -C6)alkylsulfonyl(C i -C6)alkoxy ;
R3 is, independently at each occurrence, isopropyl, tert-butyl, l-hydroxyprop-2-yl,
2-hydroxyprop-2-yl, or l-hydroxy-2-methylprop-2-yl;
R_i is, independently at each occurrence, H, (Q-C^alkyl, halogen, hydroxy, or
(Cj-C6)alkoxy;
R5 is H or (CrC6)alkyl;
R6 is H, (C C6)alkyl, halogen, hydroxy, (C C6)alkoxy, (C1-C6)alkylthio, amino,
(CrC6)alkylamino, di(C]-C6)alkylamino, (C2-C7)alkanoylamino, N-(C1-C6)alkyl- N-(C2-C7)alkanoylamino, heterocyclyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl,
(Ci-C6)alkoxy(CrC6)alkyl, (C,-C6)alkylthio(C1-C6)alkyl, amino(CrC6)alkyl,
((C1-C6)alkylamino)(Ci-C6)alkyl, (di(Ci-C6)alkylamino)(C1-C6)alkyl,
((C2-C7)alkanoylamino)(C1-C6)alkyl, (N-(C C6)alkyl-
N-(C2-C7)alkanoylamino)(C 1 -C6)alkyl, halo(C 1 -C6)alkoxy, hydroxy(C 1 -C6)alkoxy,
(C i -C6)alkoxy(C 1 -C6)alkoxy , amino(Ci -C6)alkoxy, ((C 1 -C6)alkylamino)(C 1 -C6)alkoxy,
(di(C1-C6)alkylamino)(Ci-C6)alkoxy, ((C2-C7)alkanoylamino)(CrC6)alkoxy,
(N-(Ci-C6)alkyl-N-(C2-C7)alkanoylamino)(CrC6)alkoxy, heterocyclyl(CrC6)alkoxy,
(Ci-C6)alkylsulfinyl, hydrosulfonyl, (Ci-C6)alkylsulfonyl,
(C 1 -C6)alkylsulfinyl(C \ -C6)alkoxy, hydrosulfonyl(C -C6)alkoxy, or
(C 1 -C6)alkylsulfonyl(CrC6)alkoxy ;
or a pharmaceutically acceptable salt, amide, or ester thereof.
In one embodiment the present disclosure relates to compounds of formula I,
Figure imgf000013_0001
wherein , Q2, Q3, Ri, R2, R3, R4, and R5 are as defined above.
In one embodiment the present disclosure relates to compounds of formula Π,
Figure imgf000014_0001
wherein Qi, Q2, Q3, Rj, R2, R3, and R4 are as defined above.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Qi is N, Q2 is N, and Q3 is CR6.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Qj is N, Q2 is CR6, and Q3 is N. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Q\ is N, Q2 is N+-0\ and Q3 is CR6.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Qj is N+-0 , Q2 is N, and Q3 is CR6.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Qi is N, Q2 is CR6, and Q3 is N+-0 .
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Qi is N+-0\ Q2 is CR6, and Q3 is N.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R* is, independently at each occurrence, H, (C1-C6)alkyl, halogen, or
(C C6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R4 is, independently at each occurrence, H, methyl, halogen, or methoxy. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R4 is H.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R6 is H, halogen, hydroxy, (C1-C6)alkoxy, (CrC6)alkylthio, amino,
(C1-C6)alkylamino, di(C]-C6)alkylamino, heterocyclyl, halo(Ci-C6)alkyl,
hydroxy(C1-C6)alkyl, or halo(CrC6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R6 is H, halogen, hydroxy, (Ci-C6)alkoxy, (C]-C6)alkylthio, amino,
(C1-C6)alkylamino, di(Cj-C6)alkylamino, morpholino, halo(Ci-C6)alkyl,
hydroxy(C1-C6)alkyl, or halo(CrC6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R6 is H, halogen, or (CrC6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R6 is H, halogen, or methoxy. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R6 is H.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R5 is H.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R3 is tert-butyl or l-hydroxy-2-methylprop-2-yl.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R3 is tert-butyl.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R\ is halogen, hydroxy, (Ci-C6)alkoxy, (C1-C6)alkylthio, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, heterocyclyl, haloCQ-C^alkyl, hydroxy(C!-C6)alkyl, or halo(CrC6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Ri is halogen, hydroxy, (C1-C6)alkoxy, (C1-C6)alkylthio, (CrC6)alkylamino, di(C]-C6)alkylamino, morpholino, halo(C]-C6)alkyl, hydroxy(C!-C6)alkyl, or
halo(C]-C6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R\ is halogen or (CrC6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Rj is halogen or methoxy. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R2 is halogen, hydroxy, (Ci-C6)alkoxy, (CrC6)alkylthio, amino,
(C1-C6)alkylamino, di(Ci-C6)alkylamino, heterocyclyl, halo(C]-C6)alkyl,
hydroxy(C]-C6)alkyl, or halo(C1-C6)alkoxy. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R2 is halogen, hydroxy, (Ci-C6)alkoxy, (Q-C^alkylthio, amino,
(Q-C^alkylamino, di(CrC6)alkylamino, morpholino, halo(C1-C6)alkyl, or
halo(Q-C6)alkoxy. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R2 is halogen or (Q-C^alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein R2 is halogen or methoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein Ri is halogen or (CrC6)alkoxy;
R2 is halogen or (Ci-C6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein
Qi is N, Q2 is N, and Q3 is CR6;
or Qi is N, Q2 is CR6, and Q3 is N;
Ri is halogen, hydroxy, (CrC6)alkoxy, (C]-C6)alkylthio, amino, (Ci-C6)alkylamino, di(Ci-C6)alkylamino, heterocyclyl, halo(CrC6)alkyl, hydroxy(Ci-C )alkyl, or
halo(CrC6)alkoxy;
R2 is halogen, hydroxy, (C]-C6)alkoxy, (CrC6)alkylthio, amino, (C C6)alkylamino, di(CpC6)alkylamino, heterocyclyl, halo(Ci-C6)alkyl, hydroxyCQ-C^alkyl, or
haloCd-C^alkoxy;
R3 is tert-butyl or l-hydroxy-2-methylprop-2-yl;
R4 is, independently at each occurrence, H, (C1-C6)alkyl, halogen, or (Ci-C6)alkoxy;
R5 is H or (CrC6)alkyl;
R6 is H, halogen, or (Ci-C6)alkoxy.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein
Qi is N, Q2 is N, and Q3 is CR6;
or Qi is N, Q2 is CR6, and Q3 is N;
Ri is halogen, hydroxy, (CrC6)alkoxy, (CrC6)alkylthio, (CrC6)alkylamino,
di(Ci-C6)alkylamino, morpholino, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, or
halo(CrC6)alkoxy;
R2 is halogen, hydroxy, (CrC6)alkoxy, (CrC6)alkylthio, amino, (Ci-C6)alkylamino, di(C1-C6)alkylamino, morpholino, halo(CrC6)alkyl, or halo(C!-C6)alkoxy;
R3 is tert-butyl or l-hydroxy-2-methylprop-2-yl;
R4 is, independently at each occurrence, H, methyl, halogen, or methoxy;
R5 is H or (Ci-C6)alkyl;
R6 is H, halogen, or methoxy. In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein
Qi is N, Q2 is N, and Q3 is CR6;
or Qi is N, Q2 is CR6, and Q3 is N;
Ri is halogen or (Q-C^alkoxy;
R2 is halogen or (CrC6)alkoxy;
R3 is tert-butyl;
R4 is H;
R5 is H;
R6 is H.
In one embodiment the present disclosure relates to compounds of formula I or formula Π, wherein
Qi is N, Q2 is N, and Q3 is CR6;
or Qi is N, Q2 is CR6, and Q3 is N;
R] is halogen or methoxy;
R2 is halogen or methoxy;
R3 is tert-butyl;
RUs H;
R5 is H;
R6 is H.
In one embodiment, the present disclosure relates to compounds of formula I or formula Π, wherein the compound is 4-[(5-bromo-3-methoxypyrazin-2-yl)imino]-2,6-di-tert- butylcyclohexa-2,5-dien- 1 -one, 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert- butylphenol, 2,6-di-tert-butyl-4-[(2-chloro-4-methoxypyrimidin-5-yl)amino]phenol, 2,6-di- tert-butyl-4-[(2,4-dichloropyrimidin-5-yl)amino]phenol, 2,6-di-tert-butyl-4-[(3,5- dimethoxypyrazin-2-yl)amino]phenol, 2,6-di-tert-butyl-4-[(2,4-dimethoxypyrimidin-5- yl)amino]phenol, or 2,6-di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)imino]cyclohexa-2,5- dien-l-one. The terms employed herein have the meanings indicated below. The term "carbonyl" employed in the meanings below refers to a -(C=0)- group. The term "at least one halogen" employed in the meanings below refers to one or several halogens, such as one halogen. The term "(C1-C6)alkyl", as employed herein as such or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atom(s). Representative examples of (CrC6)alkyl include, but are not limited to, methyl, ethyl, and tert-butyl. The term "halo" or "halogen", as employed herein as such or as part of another group, refers to fluorine, chlorine, bromine, or iodine.
The term "hydroxy", as employed herein as such or as part of another group, refers to a -OH group.
The term "(C1-C6)alkoxy", as employed herein as such or as part of another group, refers to an (C1-C6)alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of (Ci-C6)alkoxy include, but are not limited to, methoxy, isopropoxy, and tert-butoxy.
The term "(C1-C6)alkylthio", as employed herein as such or as part of another group, refers to an (CrC6)alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of (CrC6)alkylthio include, but are not limited to, methylthio, isopropylthio, and tert-butylthio.
The term "amino", as employed herein as such, refers to a -N¾ group.
The term "(C]-C6)alkylamino", as employed herein as such or as part of another group, refers to an (Cj-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a -NH- group. Representative examples of (C1-C6)alkylamino include, but are not limited to, methylamino, butylamino, and tert-butylamino. The term "diiCrC^alkylamino", as employed herein as such or as part of another group, refers to two (Ci-C6)alkyl groups, as defined herein, both appended to the parent molecular moiety through the same nitrogen atom. The (CrC6)alkyl groups can be identical or different. Representative examples of di(C1-C6)alkylamino include, but are not limited to, dimethylamino, diethylamino, and isopropylmethylamino.
The term "(C2-C7)alkanoyl", as employed herein as part of another group, refers to an (d-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group. Representative examples of (C2-C7)alkanoyl include, but are not limited to, acetyl, propionyl, and 4,4-dimethylpentanoyl.
The term "(C2-C7)alkanoylamino", as employed herein as such or as part of another group, refers to an (C2-C7)alkanoyl group, as defined herein, appended to the parent molecular moiety through a -NH- group. Representative examples of (C2-C7)alkanoylamino include, but are not limited to, acetylamino, propionylamino, and heptanoylamino.
The term "N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino", as employed herein as such or as part of another group, refers to an (Ci-C6)alkyl group, as defined herein, and an (C2-C7)alkanoyl group, as defined herein, both appended to the parent molecular moiety through the same nitrogen atom. Representative examples of N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino include, but are not limited to, N-acetyl-N-methylamino, N-butanoyl-N-methylamino, and N-acetyl-iV-isobutylamino.
The term "heterocyclyl", as employed herein as such or as part of another group, refers to an unsubstituted 5- or 6-membered saturated monocyclic group containing 1 or 2 ring heteroatom(s) each independently selected from N, O, and S. Representative examples of heterocyclyl include, but are not limited to, pyrrolidin-l-yl, piperidin-l-yl, and morpholino.
The term "halo(CrC6)alkyl", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an (C]-C6)alkyl group, as defined herein. When there are several halogens, the halogens can be identical or different and each halogen can be attached to different carbon atoms or several halogens can be attached to the same carbon atom. Representative examples of halo(C1-C6)alkyl include, but are not limited to, trifluoromethyl, 2-chloroethyl, and 3-bromopropyl.
The term "hydroxyCd-C^alkyl", as employed herein, refers to one or two hydroxy group(s), as defined herein, appended to the parent molecular moiety through an (Q-C6)alkyl group, as defined herein. When there are two hydroxy groups, both hydroxy groups can be attached to the same carbon atom or the hydroxy groups can be attached to different carbon atoms. Representative examples of hydroxy Q-Ce^lkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
The term "(C1-C6)alkoxy(C1-C6)alkyl", as employed herein, refers to one or two
(C1-C6)alkoxy group(s), as defined herein, appended to the parent molecular moiety through an (C1-C6)alkyl group, as defined herein. When there are two (Ci-Q)alkoxy groups, the (CrC6)alkoxy groups can be identical or different and both (CrC6)alkoxy groups can be attached to the same carbon atom or the (Q-C^alkoxy groups can be attached to different carbon atoms. Representative examples of (C1-C6)alkoxy(C1-C6)alkyl include, but are not limited to, methoxymethyl, 1-methoxyethyl, and tert-butoxymethyl.
The term "(Ci-C6)alkylthio(C1-C6)alkyl", as employed herein, refers to one or two
(C]-C6)alkylthio group(s), as defined herein, appended to the parent molecular moiety through an (Ci-C6)alkyl group, as defined herein. When there are two (C1-C6)alkylthio groups, the (Cj-C6)alkylthio groups can be identical or different and both (C1-C6)alkylthio groups can be attached to the same carbon atom or the (CrC6)alkylthio groups can be attached to different carbon atoms. Representative examples of (C1-C6)alkylthio(Ci-C6)alkyl include, but are not limited to, methylthiomethyl, l-(ethylthio)ethyl, and
4-(methylthio)butyl.
The term "amino(CrC6)alkyl", as employed herein, refers to a -NH2 group appended to the parent molecular moiety through an (CrC6)alkyl group, as defined herein. Representative examples of amino(Ci-C6)alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, and 1-aminobutyl. The term "((C1-C6)alkylamino)(C1-C6)alkyl", as employed herein, refers to an
(C]-C6)alkylamino group, as defined herein, appended to the parent molecular moiety through an (Ci-C6)alkyl group, as defined herein. Representative examples of
((C1-C6)alkylamino)(C1-C6)alkyl include, but are not limited to, methylaminomethyl, l-(methylamino)ethyl, and 3-(methylamino)propyl.
The term "(di(C]-C6)alkylammo)(Ci-C )alkyl", as employed herein, refers to a
di(C1-C6)alkylamino group, as defined herein, appended to the parent molecular moiety through an (CrC6)alkyl group, as defined herein. Representative examples of
(di(C1-C6)alkylamino)(C1-C6)alkyl include, but are not limited to, dimethylaminomethyl, 3-(dimethylamino)propyl, and l-(isopropylmethylamino)ethyl.
The term "((C2-C7)alkanoylamino)(CrC6)alkyl", as employed herein, refers to an
(C2-C7)alkanoylamino group, as defined herein, appended to the parent molecular moiety through an (Cj-C6)alkyl group, as defined herein. Representative examples of
((C2-C7)alkanoylamino)(CrC6)alkyl include, but are not limited to, acetylaminomethyl, l-(propionylamino)efhyl, and 3-(propionylamino)propyl.
The term "(N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino)(Ci-C6)alkyl", as employed herein, refers to a N-(C]-C6)alkyl-/V-(C2-C7)alkanoylamino group, as defined herein, appended to the parent molecular moiety through an (Ci-C6)alkyl group, as defined herein.
Representative examples of (N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino)(C1-C6)alkyl include, but are not limited to, N-acetyl-N-methylaminomethyl, l-(N-methyl- N-propionylamino)ethyl, and 3-(N-acetyl-N-ethylamino)propyl.
The term "halo(C1-C6)alkoxy", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an (C C6)alkoxy group, as defined herein. When there are several halogens, the halogens can be identical or different and each halogen can be attached to different carbon atoms or several halogens can be attached to the same carbon atom. Representative examples of halo(C1-C6)alkoxy include, but are not limited to, trifluoromethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, and 3-chloropropoxy. The term "hydroxy(Ci-C6)alkoxy", as employed herein, refers to one or two hydroxy group(s), as defined herein, appended to the parent molecular moiety through an
(C1-C6)alkoxy group, as defined herein. When there are two hydroxy groups, both hydroxy groups can be attached to the same carbon atom or the hydroxy groups can be attached to different carbon atoms. Representative examples of hydroxy(C1-C6)alkoxy include, but are not limited to, hydroxymethoxy, 3-hydroxypropoxy, and 3-hydroxy-2,2-dimefhylpropoxy.
The term "(Ci-C6)alkoxy(C1-C6)alkoxy", as employed herein, refers to one or two
(CrC6)alkoxy group(s), as defined herein, appended to the parent molecular moiety through an (CrC6)alkoxy group, as defined herein. The (CrC6)alkoxy groups can be identical or different. When there are two (Ci-C6)alkoxy groups appended to the parent molecular moiety through an (d-C6)alkoxy group, both (Q-C^alkoxy groups can be attached to the same carbon atom or the (C]-C6)alkoxy groups can be attached to different carbon atoms. Representative examples of (Ci-C6)alkoxy(CrC6)alkoxy include, but are not limited to, methoxymethoxy, 2-methoxyethoxy, and 3-methoxy-2,2-dimethylpropoxy.
The term "amino(C1-C6)alkoxy", as employed herein, refers to a -NH2 group appended to the parent molecular moiety through an (CrC6)alkoxy group, as defined herein.
Representative examples of amino(C1-C )alkoxy include, but are not limited to,
aminomethoxy, 3-aminopropoxy, and 3-amino-2,2-dimethylpropoxy.
The term "((C1-C6)alkylamino)(C1-C6)alkoxy", as employed herein, refers to an
(C1-C6)alkylamino group, as defined herein, appended to the parent molecular moiety through an (CrC6)alkoxy group, as defined herein. Representative examples of
((CrC6)alkylamino)(CrC6)alkoxy include, but are not limited to, methylaminomethoxy, 2-(ethylamino)ethoxy, and 2,2-dimethyl-3-(methylamino)propoxy.
The term "(di(C1-C6)alkylamino)(C1-C6)alkoxy", as employed herein, refers to a
di(Ci-C6)alkylamino group, as defined herein, appended to the parent molecular moiety through an (CrC6)alkoxy group, as defined herein. Representative examples of
(di(C1-C6)alkylamino)(Ci-C6)alkoxy include, but are not limited to, dimethylaminomethoxy, 2-(diethylamino)ethoxy, and 3-(ethylmethylamino)propoxy. The term "((C2-C7)alkanoylamino)(Ci-C6)alkoxy", as employed herein, refers to an
(C2-C7)alkanoylamino group, as defined herein, appended to the parent molecular moiety through an (CrC6)alkoxy group, as defined herein. Representative examples of
((C2-C7)alkanoylamino)(Ci-C6)alkoxy include, but are not limited to, acetylaminomethoxy, acetylaminodimethylmethoxy, and 2-(butanoylamino)ethoxy.
The term "(N-(C]-C6)alkyl-N-(C2-C7)alkanoylamino)(Ci-C6)alkoxy", as employed herein, refers to a N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino group, as defined herein, appended to the parent molecular moiety through an (C1-C )alkoxy group, as defined herein.
Representative examples of (N-(C1-C6)alkyl-N-(C2-C7)alkanoylamino)(C1-C6)alkoxy include, but are not limited to, N-acetyl-N-methylaminomethoxy, 2-(N-acetyl- N-ethylamino)ethoxy, and 3-(N-methyl-N-propionylamino)propoxy.
The term "heterocyclyl(CrC6)alkoxy", as employed herein, refers to a heterocyclyl group, as defined herein, appended to the parent molecular moiety through an (Q-C^alkoxy group, as defined herein. Representative examples of heterocyclyl(C1-C6)alkoxy include, but are not limited to, morpholinomethyl, 2-piperidin-l-ylethyl, and 3-pyrrolidin- l-ylpropyl.
The term "(C1-C6)alkylsulfinyl", as employed herein as such or as part of another group, refers to an (Ci-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a -(S=0)- group. Representative examples of (Cj-C6)alkylsulfinyl include, but are not limited to, methylsulfinyl, isopropylsulfinyl, and neopentylsulfinyl.
The term "hydrosulfonyl", as employed herein as such or as part of another group, refers to a -(0=S=0)-H group.
The term "(C1-C6)alkylsulfonyl", as employed herein as such or as part of another group, refers to an (C1-C6)alkyl group, as defined herein, appended to the parent molecular moiety through a -(0=S=0)- group. Representative examples of (Cj-C6)alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and isobutylsulfonyl.
The term "(C1-C6)alkylsulfinyl(C1-C6)alkoxy", as employed herein, refers to an
(C1-C6)alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an (Ci-C6)alkoxy group, as defined herein. Representative examples of
(C1-C6)alkylsulfinyl(C1-C6)alkoxy include, but are not limited to, methylsulfinylmethoxy, 2-(isopropylsulfinyl)ethoxy, and 2,2-dimethyl-3-(methylsulfinyl)propoxy. The term "hydrosulfonyl(CrC6)alkoxy", as employed herein, refers to a hydrosulfonyl group, as defined herein, appended to the parent molecular moiety through an (Ci-C6)alkoxy group, as defined herein. Representative examples of hydrosulfonyl(C1-C6)alkoxy include, but are not limited to, hydrosulfonylmethoxy, 3-hydrosulfonylpropoxy, and
3-hydrosulfonyl-2,2-dimethylpropoxy.
The term "(C1-C6)alkylsulfonyl(C1-C6)alkoxy", as employed herein, refers to an
(CrC6)alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an (C1-C6)alkoxy group, as defined herein. Representative examples of
(C]-C6)alkylsulfonyl(CrC6)alkoxy include, but are not limited to, methylsulfonylmethoxy, 2-(isopropylsulfonyl)ethoxy, and 2,2-dimethyl-3-(methylsulfonyl)propoxy.
Pharmaceutically acceptable salts, such as metal salts and acid addition salts, with both organic and inorganic acids, are well known in the field of pharmaceuticals. Representative examples of pharmaceutically acceptable metal salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, aluminum, and zinc salts. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, and ascorbates. Pharmaceutically acceptable amides of -NH- or -NH2 groups may be prepared by known methods using pharmaceutically acceptable carboxylic acids that are conventional in the field of pharmaceuticals. Representative examples of pharmaceutically acceptable amides of -NH- or -NH2 groups include, but are not limited to, amides formed with acetic acid, propionic acid, butyric acid, and pentanoic acid.
Pharmaceutically acceptable esters of hydroxy groups may be prepared by known methods using pharmaceutically acceptable carboxylic acids that are conventional in the field of pharmaceuticals. Representative examples of pharmaceutically acceptable esters of hydroxy groups include, but are not limited to, esters formed with acetic acid, propionic acid, butyric acid, and pentanoic acid.
The present disclosure includes within its scope all the possible geometric isomers, such as Z and E isomers (cis and trans isomers), of the compounds as well as all the possible optical isomers, such as diastereomers and enantiomers, of the compounds. Furthermore, the present disclosure includes in its scope both the individual isomers and any mixtures thereof, such as racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material, or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, such as enantiomers, from the mixture thereof, conventional resolution methods, such as fractional crystallization, may be used.
The present disclosure includes within its scope all the possible tautomers, or equilibrium mixtures thereof, of the compounds. In tautomers a hydrogen migrates from one atom of the compound to another atom of the compound. Representative examples of tautomers include, but are not limited to, keto/enol and nitroso/oxime.
The compounds of formula I or formula Π can be prepared by a variety of synthetic routes analogously to or according to methods known in the literature using suitable starting materials. Some methods useful for the preparation of the compounds of formula I or formula Π are described below.
Compounds of formula Π can be prepared as depicted in Scheme 1.
Scheme 1
Figure imgf000027_0001
In Scheme 1, Qi, Q2, Q3, R], R2, R3, and R4 are as defined above. Compound ΠΙ is reacted with compound IV in a suitable solvent, such as 1,2-dichloroethane, in the presence of a Lewis acid, such as aluminum chloride, and a base, such as pyridine.
Compounds of formula I wherein R5 is H can be prepared as depicted in Scheme 2.
Scheme 2
Figure imgf000027_0002
In Scheme 2, Qi, Q2, Q3, Rj, R2, R3, and R4 are as defined above and R5a is H. Compound Π is reduced with a suitable reducing agent in a suitable solvent, for example, with an aqueous solution of sodium dithionite in tetrahydrofuran.
Compounds of formula I wherein R5 is (Q-C^alkyl can be prepared as depicted in
Scheme 3.
Scheme 3
Figure imgf000028_0001
In Scheme 3, Qi, Q2, Q3, Rls R2, R3, R4 and R5a are as defined above and R5b is
(CrC6)alkyl. Compound la is alkylated with an (C]-C6)alkyl halide, such as (CrC6)alkyl iodide, (C!-C6)alkyl bromide or (C]-C6)alkyl chloride, in the presence of a base.
Any starting material or intermediate in the reactions to prepare compounds according to the present disclosure can be protected, if necessary, in a manner well known in the chemical field. Any protected functionality can subsequently be deprotected in a manner known in the art.
The synthetic routes described above are meant to illustrate the preparation of the compounds of formula I or formula Π and the preparation is by no means limited thereto, that is there are also other possible synthetic methods which are within the general knowledge of a person skilled in the art.
The compounds of formula I or formula II may be converted, if desired, into their pharmaceutically acceptable salt or ester form using methods well known in the art. The present disclosure will be explained in more detail by the following examples. The examples are meant for illustrating purposes only and do not limit the scope of the invention defined in the claims.
The abbreviations have the meanings indicated below.
DCM dichloromethane
RT room temperature
THF tetrahydrofuran Example 1: 4-[(5-Bromo-3-methoxypyrazin-2-yl)imino]-2,6-di-tert-butylcyclohexa-2,5- dien-l-one
A1C13 (651 mg, 4.9 mmol) was added to a solution of pyridine (0.95 ml) and 1,2- dichloroethane (25 ml). The resulting mixture was refluxed for 15 min. 2,6-Di-tert-butyl- 1,4-benzoquinone (434 mg, 1.97 mmol) and 5-bromo-3-methoxypyrazin-2-amine (420 mg, 1.97 mmol) was added and the resulting mixture was refluxed for 18 h. After cooling to RT, the mixture was filtered through celite. Celite was washed with DCM and the combined organic phase was concentrated under reduced pressure. The product was purified using column chromatography. Yield: 80 mg
1H NMR (CDC13): 1.21 (9H, s), 1.30 (9H, s), 4.07 (3H, s), 6.90 (1H, m), 7.07 (1H, m), 8.10 (1H, s)
Example 2: 4-[(5-Bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert-butylphenol 3,5-Dibromo-2-aminopyrazine
N-Bromosuccinimide (5.1 g, 28.7 mmol) was added slowly and portion wise to a mixture of aminopyrazine (1.3 g, 13.6 mmol) in dimethylsulfoxide (11 ml) and water (17 ml). During the addition of N-bromosuccinimide, the temperature of the reaction mixture was maintained below 15 °C. After the addition, the reaction mixture was stirred for 16 h at RT. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 10 % Na2C03 solution followed by washing with water and brine. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo to obtain crude product. The product was purified using column chromatography. Yield: 1.51 g
1H NMR (CDC13): 5.04 (2H, s), 8.03 (1H, s) 5-Bromo-3-methoxypyrazin-2-amine
A mixture of 3,5-dibromo-2-aminopyrazine (750 mg, 2.9 mmol), sodium methoxide (400 mg, 7.4 mmol) and methanol (20 ml) was refluxed for 16 h. The solvent was removed and the residue was purified using column chromatography. Yield: 450 mg
1H NMR (CDCI3): 3.99 (3H, s), 4.76 (2H, s), 7.63 (1H, s)
4-[(5-Bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert-butyIphenol A1C13 (657 mg, 4.93 mmol) was added to a solution of pyridine (0.9 ml) and 1,2- dichloroethane (25 ml). The resulting mixture was refluxed for 15 min. 2,6-di-tert-butyl-l,4- benzoquinone (1.08 g, 4.93 mmol) and 5-bromo-3-methoxypyrazin-2-amine (500 mg, 2.46 mmol) was added and the resulting mixture was refluxed for 18 h. After cooling to RT, the mixture was filtered through celite. Celite was washed with DCM and the combined organic phase was concentrated under reduced pressure. The residue was dissolved in THF. Aqueous saturated solution of sodium dithionite was added under ice cooling until the reaction mixture was colorless. The resulting mixture was stirred at RT for 2 h. The mixture was extracted with DCM. The organic layer was separated and dried over sodium sulfate and concentrated under reduced pressure. The product was purified using column chromatography. Yield: 150 mg
1H NMR (CDC13): 1.44 (18H, s), 4.06 (3H, s), 5.01 (1H, s), 6.77 (1H, s), 7.40 (2H, s), 7.41 (1H, s) Example 3: 2,6-Di-tert-butyl-4-[(2-chloro-4-methoxypyrimidin-5-yI)amino]phenol
2-Chloro-4-methoxypyrimidin-5-amine
2-Chloro-4-methoxypyrimidin-5-amine was synthesized using the same method as described for 5-bromo-3-methoxypyrazin-2-amine in Example 2. 200 mg (1.2 mmol) of dichloropyrimidin-5-amine, 263 mg (4.9 mmol) of sodium methoxide, and 30 ml of methanol was used. Yield: 171 mg
1H NMR (CDCI3): 4.04 (3H, s), 7.76 (1H, s)
2,6-Di-tert-butyl-4-[(2-chloro-4-methoxypyrimidin-5-yl)amino]phenol
2,6-Di-tert-butyl-4-[(2-chloro-4-methoxypyrimidin-5-yl)amino]phenol was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di- tert-butylphenol in Example 2. 358 mg (2.67 mmol) of A1C13, 0.51 ml of pyridine, 20 ml of 1,2-dichloroethane, 235 mg (1.07 mmol) of 2,6-di-tert-butyl-l,4-benzoquinone, and 170 mg (1.07 mmol) of 2-chloro-4-methoxypyrimidin-5-amine was used. Reaction time in the imine formation stage was 48 h. Yield: 30 mg
1H NMR (CDCI3): 1.40 (18H, s), 4.10 (3H, s), 5.08 (1H, s), 5.62 (1H, s), 6.97 (2H, s), 7.98 (1H, s) Example 4: 2,6-Di-tert-butyl-4-[(2,4-dichloropyrimidin-5-yI)amino]phenol
2,6-Di-tert-butyl-4-[(2,4-dichloropyrimidin-5-yl)amino]phenol was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert- butylphenol in Example 2. 406 mg (3.04 mmol) of A1C13, 0.59 ml of pyridine, 30 ml of 1,2- dichloroethane, 268 mg (1.22 mmol) of 2,6-di-tert-butyl-l,4-benzoquinone, and 200 mg (1.22 mmol) of 2,4-dichloropyrimidin-5-amine was used. Reaction time in the imine formation stage was 48 h. Yield: 60 mg
1H NMR (CDC13): 1.42 (18H, s), 5.22 (1H, s), 5.84 (1H, s), 6.99 (2H, s), 8.14 (1H, s) Example 5: 2,6-Di-tert-butyI-4-[(3,5-dimethoxypyrazin-2-yl)amino]phenol 3,5-Dimethoxypyrazin-2-amine
3.5- Dibromo-2-aminopyrazine (1 g, 3.96 mmol), sodium methoxide (2.14 g, 23.7 mmol) and copper powder (1.5 g, 23.7 mmol) were introduced together in a screw cap vial of Pyrex glass (sealed tube) with 30 ml methanol and a stirring rod. The vial was tightly closed and put in an oil bath at 140 °C and stirred for 16 h. The mixture was filtered through celite pad and washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain crude product. The crude product was directly used for the next step. Yield: 640 mg
2.6- Di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)amino]phenol
2,6-Di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)amino]phenol was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert- butylphenol in Example 2. 1.37 g (10.3 mmol) of A1C13, 1.99 ml of pyridine, 30 ml of 1,2- dichloroethane, 909 mg (4.12 mmol) of 2,6-di-tert-butyl-l,4-benzoquinone, and 640 mg (4.12 mmol) of 3,5-dimethoxypyrazin-2-amine was used. Yield: 250 mg
1H NMR (CDCI3): 1.44 (18H, s), 3.88 (3H, s), 4.03 (3H, s), 4.90 (1H, s), 6.47 (1H, s), 7.30 (1H, s), 7.40 (2H, s) Example 6: 2,6-Di-tert-butyI-4-[(2,4-dimethoxypyrimidin-5-yl)amino]phenol 2,4-Dimethoxypyrimidin-5-amine 2.4- Dimethoxypyrimidin-5-amine was synthesized using the same method as described for
3.5- dimethoxypyrazin-2-amine in Example 5. 200 mg (1.22 mmol) of 2,4- dichloropyrimidin-5-amine, 658 mg (12.2 mmol) of sodium methoxide, 464 mg
(7.31 mmol) of copper powder, and 20 ml of methanol was used. Yield: 184 mg
2.6- Di-tert-butyl-4-[(2,4-dimethoxypyrimidin-5-yI)amino]phenol
2,6-Di-tert-butyl-4-[(2,4-dimethoxypyrimidin-5-yl)amino]phenol was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert- butylphenol in Example 2. 387 mg (2.9 mmol) of A1C13, 0.55 ml of pyridine, 20 ml of 1,2- dichloroethane, 255 mg (1.16 mmol) of 2,6-di-tert-butyl-l,4-benzoquinone, and 180 mg (1.16 mmol) of 2,4-dimethoxypyrimidin-5-amine was used. Reaction time in the imine formation stage was 17 h. Yield: 25 mg
1H NMR (CDC13): 1.41 (18H, s), 3.93 (3H, s), 4.05 (3H, s), 4.93 (1H, s), 5.28 (1H, s), 6.90 (2H, s), 7.97 (lH, s)
Example 7: 2,6-Di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)imino]cyclohexa-2,5-dien- 1-one
2,6-Di-tert-butyl-4-[(3,5-dimethoxypyrazin-2-yl)imino]cyclohexa-2,5-dien-l-one was synthesized using the same method as described for 4-[(5-bromo-3-methoxypyrazin-2- yl)imino]-2,6-di-tert-butylcyclohexa-2,5-dien-l-one in Example 1. 861 mg (6.45 mmol) of AICI3, 1.24 ml of pyridine, 25 ml of 1,2-dichloroethane, 568 mg (2.58 mmol) of 2,6-di-tert- butyl-l,4-benzoquinone, and 400 mg (2.58 mmol) of 3,5-dimethoxypyrazin-2-amine was used in the reaction. Yield: 503 mg
1H NMR (CDC¾): 1.23 (9H, s), 1.30 (9H, s), 4.01 (3H, s), 4.08 (3H, s), 7.09 (1H, m), 7.32 (1H, m), 7.70 (1H, s)
As already mentioned hereinbefore, the compounds of formula I or formula Π show interesting pharmacological properties, namely they exhibit enhanced CytC derived peroxidase inhibiting activity and are not pro-oxidative. Said properties are demonstrated with the pharmacological tests presented below.
Experiment 1: Determination of pharmacological activity against CytC derived peroxidase The peroxidase activity of CytC was studied using 2',7'-dichlorofluorescin (DCF; Fluka) as a probe. The measurements were made in 96-well plate containing 10 μΜ DCF, 200 μΜ hydrogen peroxide (Pedrogen 30, Riedel de Haen), and 0.1 μΜ CytC (from horse heart, Fluka) per well in 50 mM sodium phosphate buffer pH 7.8. The increase in DCF
fluorescence was measured on Wallac Victor 1420 multilabel counter at 480 nm / 510 nm (excitation/emission) for 60 min. The compounds were tested at 0 μΜ, 1 μΜ, 5 μΜ, 10 μΜ, and 50 μΜ final concentrations. Two parallels of each compound at each concentrations tested were run. The rate of peroxidation was calculated as slope of the linear interval between 16 min and 31 min using the average value of two wells. Background was determined as the rate of non-catalytical oxidation of DCF by hydrogen peroxide in the absence of CytC. The background was subtracted from the rate of CytC catalyzed peroxidation and the rate of CytC catalyzed peroxidation in the absence of a compound was set to 100 %. Data were saved in Excel format and expressed as apparent target activity at a particular compound concentration.
The results are shown in Figure 1. The results show that the compounds of formula I or formula Π are capable of inhibiting CytC derived peroxidase activity. Experiment 2: Determination of efficacy against glutamate induced glutathione depletion in PC12 cells
Compounds were studied for their potency to inhibit oxidative stress induced cell death. As undifferentiated PC 12 cells do not even express glutamate receptors, glutamate toxicity can be used as a model for oxidative stress-induced cell death in which glutamate causes glutathione depletion and oxidative stress independent of excitotoxicity (for example, Lewerenz, J. et al. J. Neurochem., 98 (2006) 916).
Undifferentiated PC 12 cells (ATCC) were plated in 96-well plates (10,000 cells/well in 100 μΐ medium (Dulbecco's Modified Eagle Medium GlutaMAX Gibco, supplemented with 5 % fetal bovine serum (FBS; Gibco, #10270-106) and 5 % horse serum (HS; Gibco, #26050-088))). Medium was replaced 48 h after plating with 100 μΐ serum-free medium containing various concentrations of toxin to first establish glutamate dose response. The concentration of glutamate that yielded 70-90 % cytotoxicity in vehicle treated wells was selected for screening potential cytoprotective effects of study compounds.
Compounds were studied at high (0-10 μΜ) and low (0-80 nM) concentration ranges.
Compounds were plated on cells at the same time as glutamate was added. Controls included cells exposed to plain medium (scaled to 100 % viability), glutamate only, or study compounds alone without glutamate to assess potential cytotoxicity of the study compounds on PC 12 cells. Six parallel wells were exposed. After 24-h incubation resazurin viability assay was performed.
Resazurin is a dye producing highly fluorescent resorufin when reduced by oxidoreductases within viable cells. Measurement of resazurin fluorescence is therefore an indicator of the viability of the cell. Following the glutamate exposure, medium was removed and replaced with 100 μΐ of 10 μΜ pre-warmed resazurin (Sigma, R7017). The working solution of resazurin was prepared from 50 mM resazurin in Hank's Buffered Salt Solution (HBSS; Lonza, BE10-547F) stock solution. The plates were incubated for 2 h at 37 °C, 5 % C02. Resorufin fluorescence was measured at 530 nm / 590 nm (excitation/emission) using Victor 1420 multilabel reader. Data were saved in Excel format. The fluorescence of the blank (no cells) was subtracted from all values. Control wells which contained cells that were not exposed to glutamate were normalized to 100 %. The data were presented as a percentage of viable cells as a function of compound concentration (in the presence or absence of glutamate).
The Student's T-test was used to determine whether the difference between the means for two measurement groups (treatment group at selected concentration vs. vehicle treated cells) was statistically significant. P values were calculated by embedded Microsoft Excel 2007 function using two-tailed distribution and two-sample equal variance T-test.
The results are shown in Figure 2a, Figure 2b, Figure 2c, and Figure 2d. The results show that the compounds of formula I or formula Π are capable of inhibiting oxidative stress induced cell death and are not cytotoxic on PC 12 cells when incubated on PC 12 cells without glutamate. Experiment 3: Determination of inhibitory effects against lipopoly saccharide induced nitric oxide, tumor necrosis factor a, monocyte chemotactic protein 1, and
interleukin-6 production in BV2 cells Activated glial cells coexist with degenerating neurons in all neurodegenerative diseases. Bacterial lipopolysaccaride (LPS) is a widely used stimulant of glial cells leading to the release of pro-inflammatory mediators and release of CytC from mitochondria to cytosol. Compounds were studied for their potency to suppress the production and/or secretion of nitric oxide (NO), tumor necrosis factor a (TNFa), monocyte chemotactic protein 1
(MCP-1), and interleukin-6 (IL-6), which are pro-inflammatory mediators. Microglial BV2 cell line was exposed to LPS in the presence or absence of study compounds, and the amount of NO, TNFa, MCP-1, and IL-6 in the culture media was assayed.
The murine microglial BV2 cell line was grown in RPMI-1640 (Sigma, R0883) medium containing 10 % heat inactivated FBS (Gibco, 10270) supplemented with L-glutamine
(Gibco, 25030) at 4 mM final concentration and 5 μg ml of gentamicin (Sigma, G1272) at 37 °C in a humidified atmosphere of 5 % C02. Cultured BV2 cells were then stimulated with 50 ng/ml LPS (Sigma, L2630) for 24 h in the absence or presence of various concentrations (2.5 μΜ, 5 μΜ, 10 μΜ, and 20 μΜ) of study compounds. NO release was analyzed as nitrite, which is the primary stable and nonvolatile breakdown product of NO by Griess reagent system (Promega) according to manufacturer's instructions. The viability of BV2 cells, as assessed by resazurin assay as described in Experiment 2, in the presence of increasing concentrations of study compounds was noted to be unchanged. The NO release from BV2 cells exposed to LPS only was normalized to 100 %. TNFa, MCP-1, and IL-6 were measured using cytometric bead array CBA Mouse Inflammation Kit (BD) according to manufacturer's instructions.
The results are shown in Figure 3a and Figure 3b. The results show that the compounds of formula I or formula Π are capable of suppressing the production and/or secretion of NO, TNFa, MCP- 1 , and IL-6.
Experiment 4: Determination of neuroprotective effects in vivo Adult male Balb/cA mice (25-30 g body weight) were maintained at National Laboratory Animal Center, Kuopio, Finland. The mice were housed in standard temperature
(22 °C ± 1 °C) and light-controlled (light period 07:00-21 :00) environment with ad libitum access to food and water. Immediately prior to the surgery, each subject was anesthetized with 5 % halothane for induction and 1 % for maintenance in carrier gas of 02 (30 %) and N20 (70 %). Permanent focal cerebral ischemia was produced by cauterizing the middle cerebral artery (MCA) at the level of the inferior cerebral vein. The body temperature was maintained at 36-37 °C during the surgery with a heating pad. The left temporoparietal region of the head was shaved and a midline incision was made between the orbit and ear to expose the skull. A small burr hole (diameter 1 mm) was drilled in the temporal lobe just above the MCA and saline was applied to the area throughout the procedure to prevent heat injury. The inner layer of the skull and the dura were carefully removed by the forceps and the MCA was occluded permanently by electrocoagulation. The burr hole was filled with porous material (Spongostan, Johnson & Johnson, New Brunswick, NJ, United States) and the wounds were sutured and the mice were let to regain full consciousness before returning them to the cage. All the treatments and surgical procedures were approved by the Ethical Committee of the State Provincial Office of Southern Finland.
The treatments with study compounds were started at 12 h prior to MCA occlusion and continued thereafter at 12 h intervals until 60 h post-occlusion. The compounds were formulated in 0.5 % carboxymethylcellulose (CMC) at 9 mg/ml and administered p.o. at the dose of 30 mg/kg. Vehicle treated mice received an equal volume of CMC only.
Mice were imaged with magnetic resonance imaging (MRI) 72 h after the lesion. MRI data were acquired at 4.7 T (Magnex Scientific Ltd., Abington, United Kingdom) interfaced to a Varian UNITYINOVA console (Varian, Inc., Palo Alto, CA, United States). A quadrature volume coil (Rapid Biomedical, Germany) was used for transmission and a surface coil for reception. Mice anesthetized with isoflurane (1 % during imaging, carrier gas of 02 (30 %) and N20 (70 %)) were fixed to a head holder and positioned in the magnet bore in a standard orientation relative to gradient coils. For determination of the volume of the lesion, T2-weighted multi-slice (13 continuous slices) images were acquired using a double spin- echo sequence with adiabatic refocusing pulses TR = 2 s, total TE = 50 ms, matrix size of 256 x 128, FOV of 25.6 mm2 x 25.6 mm2, and a slice thickness of 0.8 mm, 2 averages. After MRI, the mice were killed with C02, brains quickly removed and checked for proper site of MCA occlusion. The lesions were outlined manually from T2-weighted MRI images using MATLAB software. The lesion volumes were calculated by Shuaib's indirect formula (Shuaib, A. et al. Stroke, 33 (2002) 3033). Statistical analyses were performed and P values calculated by embedded Microsoft Excel 2007 function using two-tailed distribution and two-sample equal variance T-test.
The results are shown in Figure 4. The results show that the compounds of formula I or formula Π are capable of providing neuroprotective effects in vivo.
The compounds of formula I or formula Π exhibit CytC derived peroxidase inhibiting activity. The present disclosure thus provides compounds for use as a medicament.
Compounds for use in the treatment of a neurodegenerative disorder are also provided. Furthermore, a method for the treatment of a neurodegenerative disorder is provided. In said method a therapeutically effective amount of at least one compound of formula I or formula Π is administered to a mammal, such as a human, in need of such treatment. Use of the compounds of formula I or formula Π for the manufacture of a medicament for the treatment of a neurodegenerative disorder is also provided. In one embodiment the aforementioned neurodegenerative disorder is Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, familial Creutzfeld- Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome,
Creutzfeld- Jakob disease, sporadic fatal insomnia, kuru, variant Creutzfeld- Jakob disease, mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, mixed dementia (combination of Alzheimer's disease and vascular dementia), HIV-associated dementia, Lewy body dementia,
Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, chronic alcoholism, retinitis pigmentosa, deficit in hearing due to degeneration of vestibular and cochlear cells, deficit in balance due to degeneration of vestibular and cochlear cells, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, a neurodegenerative disease associated with neonatal hypoxia-ischemia, or a neurodegenerative disease associated with ischemia during coronary artery bypass grafting. In one embodiment the aforementioned neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, or a neurodegenerative disease associated with neonatal hypoxia-ischemia.
The compounds of formula I or formula Π can be administered, for example, enterally, topically or parenterally by means of any pharmaceutical formulation useful for said administration and comprising as an active ingredient at least one compound of formula I or formula Π in pharmaceutically acceptable and effective amounts together with
pharmaceutically acceptable diluents, carriers and/or excipients known in the art.
The therapeutic dose to be given to a patient in need of the treatment will vary depending on the compound being administered, the age and the sex of the subject being treated, the particular condition being treated, as well as the route and method of administration, and may be determined by a person skilled in the art. A typical dosage for oral administration is from 10 ng kg to 100 mg/kg per day and for parenteral administration from 1 ng/kg to 10 mg/kg for an adult mammal. The compounds according to the present disclosure are given to a patient as such or in combination with one or more other active ingredients and/or suitable pharmaceutical excipients. The latter group comprises conventionally used excipients and formulation aids such as fillers, binders, disintegrating agents, lubricants, solvents, gel forming agents, emulsifiers, stabilizers, colorants, and/or preservatives.
The compounds of formula I or formula Π are formulated into dosage forms using commonly known pharmaceutical manufacturing methods. The dosage forms can be, for example, tablets, capsules, granules, suppositories, emulsions, suspensions, or solutions. Depending on the route of administration and the galenic form, the amount of the active ingredient in the formulation can typically vary between 0.01 % and 100 % (w/w).
As already mentioned hereinbefore, the compounds of formula I or formula Π can be given together with one or more other active ingredients, each in its own composition or two or more of the active ingredients combined in a single composition. The compounds of formula I or formula II can be given together with one or more other active ingredients in the treatment of, for example, MS, ALS, or a neurodegenerative disease associated with ischemic stroke. In the treatment of MS the compounds of formula I or formula Π can be given together with one or more immunomodulators, such as methylprednisolone, interferon beta, natalizumab, glatiramer, fingolimod, dimethyl fumarate, or teriflunomide. In the treatment of ALS the compounds of formula I or formula II can be given together with riluzole. In the treatment of a neurodegenerative disease associated with ischemic stroke the compounds of formula I or formula Π can be given together with one or more thrombolytic agents, such as alteplase, or as an adjunct to thrombectomy.
A person skilled in the art will appreciate that the embodiments described in the present disclosure can be modified without departing from the inventive concept. A person skilled in the art also understands that the present disclosure is not limited to the particular embodiments disclosed but is intended to also cover modifications of the embodiments that are within the spirit and scope of the present disclosure.

Claims

1. A compound of formula I or formula Π,
Figure imgf000040_0001
wherein
two of Qi, Q2, or Q3 are N, and one of Qi, Q2, or Q3 is CR6;
or one of Qi , Q2, or Q3 is N, one of Qi , Q2, or Q3 is N+-0\ and one of Qi, Q2, or
Q3 is CR6;
Ri is (CrC6)alkyl, halogen, hydroxy, (C1-C6)alkoxy, (Q-C^alkylthio, amino, (Ci-C6)alkylamino, di(C1-C6)alkylamino, (C2-C7)alkanoylamino, N-(Ci-C6)alkyl- N-(C2-C7)alkanoylamino, heterocyclyl, halo(C!-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, amino(C1-C6)alkyl, ((C1-C6)alkylamino)(C1-C6)alkyl, (di(Ci-C6)alkylamino)(C C6)alkyl, ((C2-C7)alkanoylamino)(C1 -C6)alkyl, (N-(C C6)alkyl- N-(C2-C7)alkanoylamino)(C C6)alkyl, haloCQ-Q alkoxy,
hydroxy(C 1 -C6)alkoxy, (C 1 -C6)alkoxy(C 1 -C6)alkoxy, amino(C 1 -C6)alkoxy,
((C1-C6)alkylamino)(C]-C6)alkoxy, (di(C1-C6)alkylamino)(Ci-C6)alkoxy,
((C2-C7)alkanoylamino)(C1-C6)alkoxy, (N-(Q-C6)aikyl- N-(C2-C7)alkanoylamino)(CrC6)alkoxy, heterocyclyl(C1-C6)alkoxy, (Ci-C6)alkylsulfinyl, hydrosulfonyl, (Ci-C6)alkylsulfonyl,
(C i -C6)alkylsulfinyl(C 1 -C6)alkoxy, hydrosulfony Q -C6)alkoxy, or
(C]-C6)alkylsulfonyl(Ci-C6)alkoxy;
R2 is (Ci-C6)alkyl, halogen, hydroxy, (C1-C6)alkoxy, (C]-C6)alkylthio, amino, (CrC6)alkylamino, di(Ci-C6)alkylamino, (C2-C7)alkanoylamino, N-(CrC6)alkyl- N-(C2-C7)alkanoylamino, heterocyclyl, halo(C]-C6)alkyl, hydroxy(CrC6)alkyl, (C i -C6)alkoxy(C i -C6)alkyl, (C i -C6)alkylthio(C ] -C6)alkyl, amino(C i -C6)alkyl, ((C1-C6)alkylamino)(Ci-C6)alkyl, (di(C1-C6)alkylamino)(C1-C6)alkyl,
((C2-C7)alkanoylamino)(C1-C6)alkyl, (N-(Ci-C6)alkyl- N-(C2-C7)alkanoylamino)(Ci-C6)alkyl, halo(CrC6)alkoxy,
hydroxy(Ci -C6)alkoxy, (C i -C6)alkoxy(C i -C6)alkoxy, amino(C i -C6)alkoxy, ((C1-C6)alkylamino)(Ci-C6)alkoxy, (di(C1-C6)alkylamino)(C1-C6)alkoxy, ((C2-C7)alkanoylamino)(CrC6)alkoxy, (N-(C1-C6)alkyl- N-(C2-C7)alkanoylamino)(C1-C6)alkoxy, heterocyclyl(Ci-C6)alkoxy,
(Ci-C6)alkylsulfinyl, hydrosulfonyl, (C!-C6)alkylsulfonyl,
(Ci-C6)alkylsulfinyl(C1-C6)alkoxy, hydrosulfonyl(C1-C6)alkoxy, or
(Ci-C6)alkylsulfonyl(C1-C6)alkoxy;
R3 is, independently at each occurrence, isopropyl, tert-butyl,
l-hydroxyprop-2-yl,
2-hydroxyprop-2-yl, or l-hydroxy-2-methylprop-2-yl;
R4 is, independently at each occurrence, H, (Q-C^alkyl, halogen, hydroxy, or
(C]-C )alkoxy;
R5 is H or (CrQ alkyl;
R6 is H, (CrC6)alkyl, halogen, hydroxy, (CrC6)alkoxy, (C1-C6)alkylthio, amino, (Ci-C )alkylamino, di(Ci-C )alkylamino, (C2-C7)alkanoylamino, N-(Ci-C6)alkyl- N-(C2-C7)alkanoylamino, heterocyclyl, halo(C1-C6)alkyl, hydroxy(C]-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C C6)alkylthio(C1-C6)alkyl, amino(C1-C6)alkyl, ((C i -C6)alkylamino)(C \ -C6)alkyl, (di(C i -C6)alkylamino)(C i-C6)alkyl,
((C2-C7)alkanoylamino)(C C6)alkyl, (N-(C1-C6)alkyl- N-(C2-C7)alkanoylamino)(C]-C6)alkyl, halo(C1-C6)alkoxy,
hydroxy(C i -C6) alkoxy , (C -C6) alkoxy(C ] -C6)alkoxy , amino (C i -C6)alkoxy , ((Ci -C6)alkylamino)(C1 -C6)alkoxy, (di(C ] -C6)alkylamino)(C i -C6)alkoxy, ((C2-C7)alkanoylamino)(Ci-C6)alkoxy, (N-Cd-C^alkyl- N-(C2-C7)alkanoylamino)(C1-C6)alkoxy, heterocyclyl(Ci-C6)alkoxy,
(CrC6)alkylsulfinyl, hydrosulfonyl, (C1-C6)alkylsulfonyl,
(C i -C6)alkylsulfinyl(C i -C6)alkoxy , hydrosulf onyl(C i -C6)alkoxy, or
(C ! -C6)alkylsulfonyl(C i -C6)alkoxy ;
or a pharmaceutically acceptable salt, amide, or ester thereof. A compound according to claim 1 , wherein the compound is a compound of
Figure imgf000042_0001
wherein Qi, Q2, Q3, R], R2, R3, R4, and R5 are as defined in claim 1.
3. A compound according to claim 1, wherein the compound is a compound of
Figure imgf000042_0002
wherein Qi, Q2, Q3, Ri, R2, R3, and R4 are as defined in claim 1.
4. A compound according to any one of claims 1 to 3, wherein Qj is N, Q2 is N, and Q3 is CR6.
A compound according to any one of claims 1 to 3, wherein Qj is N, Q2 is CR6, and Q3 is N.
A compound according to any one of claims 1 to 3, wherein Qj is N, Q2 is N+-0", and Q3 is CR6.
A compound according to any one of claims 1 to 3, wherein Q is N+-0", Q2 is N, and Q3 is CR6.
A compound according to any one of claims 1 to 3, wherein Qi is N, Q2 is CR6, and Q3 is N+-0".
A compound according to any one of claims 1 to 3, wherein Qj is N+-0", Q2 is CR6, and Q3 is N.
10. A compound according to any one of claims 1 to 9, wherein R4 is, independently at each occurrence, H, (Ci-C6)alkyl, halogen, or (CrC6)alkoxy.
1 1. A compound according to claim 10, wherein R4 is, independently at each
occurrence, H, methyl, halogen, or methoxy.
12. A compound according to claim 11, wherein R4 is H.
13. A compound according to any one of claims 1 to 12, wherein R6 is H, halogen, hydroxy, (Ci-C6)alkoxy, (Q-C6)alkylthio, amino, (CrC6)alkylamino, di(C]-C6)alkylamino, heterocyclyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, or halo(C i -C6)alkoxy.
14. A compound according to claim 13, wherein R6 is H, halogen, hydroxy,
(C]-C6)alkoxy, (C]-C6)alkylthio, amino, (CrC6)alkylamino,
di(C1-C6)alkylamino, morpholino, halo(C]-C6)alkyl, hydroxy(C!-C6)alkyl, or halo(Ci-C6)alkoxy.
15. A compound according to claim 14, wherein R6 is H, halogen, or (Ci-C6)alkoxy.
16. A compound according to claim 15, wherein R6 is H, halogen, or methoxy.
17. A compound according to claim 16, wherein R6 is H.
18. A compound according to any one of claims 1 to 17, wherein R5 is H.
19. A compound according to any one of claims 1 to 18, wherein R3 is tert-butyl or
1 -hydroxy-2-methylprop-2-yl.
20. A compound according to claim 19, wherein R3 is tert-butyl.
21. A compound according to any one of claims 1 to 20, wherein
Figure imgf000043_0001
is halogen, hydroxy, (C]-C6)alkoxy, (C]-C6)alkylthio, amino, (Ci-C )alkylamino, di(C1-C6)alkylamino, heterocyclyl, halo(CrC6)alkyl, hydroxy(C1-C6)alkyl, or halo(Ci-C6)alkoxy.
22. A compound according to claim 21, wherein Ri is halogen, hydroxy, (CrC6)alkoxy, (Ci-C6)alkylthio, (C1-C6)alkylamino, diCQ-C^alkylamino, morpholino, halo(C1-C6)alkyl, hydroxy (Cj-C6)alkyl, or halo(C]-C6)alkoxy.
23. A compound according to claim 22, wherein Rj is halogen or (Ci-C6)alkoxy.
24. A compound according to claim 23, wherein Ri is halogen or methoxy.
25. A compound according to any one of claims 1 to 24, wherein R2 is halogen, hydroxy, (CrC6)alkoxy, (C]-C6)alkylthio, amino, (C]-C6)alkylamino, di(C1-C6)alkylamino, heterocyclyl, halo(Ci-C6)alkyl, hydroxy(CrC6)alkyl, or halo(C1-C6)alkoxy.
26. A compound according to claim 25, wherein R2 is halogen, hydroxy,
(C1-C6)alkoxy, (Ci-C6)alkylthio, amino, (Ci-C6)alkylamino,
di(C1-C6)alkylamino, morpholino, halo(Ci-C6)alkyl, or halo(C1-C6)alkoxy.
27. A compound according to claim 26, wherein R2 is halogen or (Ci-C6)alkoxy.
28. A compound according to claim 27, wherein R2 is halogen or methoxy.
29. A compound according to any one of claims 1 to 20, wherein
Ri is halogen or (Ci-C6)alkoxy;
R is halogen or (Ci-C6)alkoxy.
30. A compound according to any one of claims 1 to 3, wherein
Cj! is N, Q2 is N, and Q3 is CR6;
or Qi is N, Q2 is CR6, and Q3 is N;
Ri is halogen, hydroxy, (C1-C6)alkoxy, (CrC6)alkylthio, amino,
(C!-C6)alkylamino, di(CrC6)alkylamino, heterocyclyl, halo(C1-C6)alkyl, hydroxy(Ci-C6)alkyl, or halo(Ci-C6)alkoxy;
R2 is halogen, hydroxy, (Ci-C6)alkoxy, (C]-C6)alkylthio, amino,
(C Ceialkylamino, di(Ci-C6)alkylamino, heterocyclyl, halo(C1-C6)alkyl, hydroxy(CrC6)alkyl, or halo(CrC6)alkoxy;
R3 is tert-butyl or l-hydroxy-2-methylprop-2-yl;
R4 is, independently at each occurrence, H, (C]-C6)alkyl, halogen, or (CrC6)alkoxy;
R5 is H or (CrC6)alkyl;
R6 is H, halogen, or (CrC6)alkoxy.
31. A compound according to claim 30, wherein
Q] is N, Q2 is N, and Q3 is CR6;
or Q] is N, Q2 is CR6, and Q3 is N;
Ri is halogen, hydroxy, (C1-C6)alkoxy, (Ci-C6)alkylthio, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, halo(Ci-C6)alkyl, hydroxy(C1-C6)alkyl, or halo(C i -C6)alkoxy ;
R2 is halogen, hydroxy, (CrC6)alkoxy, (CrC6)alkylthio, amino,
(CrC6)alkylamino, di(C]-C6)alkylamino, morpholino, halo(C1-C6)alkyl, or halo(C i -C6)alkoxy ;
R3 is tert-butyl or l-hydroxy-2-methylprop-2-yl;
R4 is, independently at each occurrence, H, methyl, halogen, or methoxy;
R5 is H or (CrC6)alkyl;
R6 is H, halogen, or methoxy.
32. A compound according to claim 31, wherein
Qi is N, Q2 is N, and Q3 is CR6;
or Qj is N, Q2 is CR6, and Q3 is N;
Ri is halogen or (Ci-C6)alkoxy;
R2 is halogen or (CpC6)alkoxy;
R3 is tert-butyl;
R4 is H;
R5 is H;
R6 is H.
33. A compound according to claim 32, wherein
Qi is N, Q2 is N, and Q3 is CR6;
or is N, Q2 is CR6, and Q3 is N;
Ry is halogen or methoxy;
R2 is halogen or methoxy;
R3 is tert-butyl; R4 is H;
R5 is H;
R6 is H.
34. A compound according to any one of claims 30 to 33, wherein Qi is N, Q is N, and Q3 is CR6.
35. A compound according to any one of claims 30 to 33, wherein Qi is N, Q2 is CR6, and Q3 is N.
36. A compound according to claim 1, wherein the compound is 4-[(5-bromo-3- methoxypyrazin-2-yl)imino]-2,6-di-tert-butylcyclohexa-2,5-dien-l-one, 4-[(5- bromo-3-methoxypyrazin-2-yl)amino]-2,6-di-tert-butylphenol, 2,6-di-tert-butyl- 4-[(2-chloro-4-methoxypyrimidin-5-yl)amino]phenol, 2,6-di-tert-butyl-4-[(2,4- dichloropyrimidin-5-yl)amino]phenol, 2,6-di-tert-butyl-4-[(3,5- dimethoxypyrazin-2-yl)amino]phenol, 2,6-di-tert-butyl-4-[(2,4- dimethoxypyrimidin-5-yl)amino]phenol, or 2,6-di-tert-butyl-4-[(3,5- dimethoxypyrazin-2-yl)imino]cyclohexa-2,5-dien-l-one.
37. A compound according to any one of claims 1 to 36 for use as a medicament.
38. A compound according to any one of claims 1 to 36 for use in the treatment of a neurodegenerative disorder.
39. A compound according to claim 38, wherein the neurodegenerative disorder is Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, familial Creutzfeld- Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, Creutzfeld- Jakob disease, sporadic fatal insomnia, kuru, variant Creutzfeld-Jakob disease, mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, mixed dementia (combination of Alzheimer's disease and vascular dementia), HTV-associated dementia, Lewy body dementia, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, chronic alcoholism, retinitis pigmentosa, deficit in hearing due to degeneration of vestibular and cochlear cells, deficit in balance due to degeneration of vestibular and cochlear cells, a neurodegenerative disease associated with traumatic brain injury, a
neurodegenerative disease associated with spinal cord injury, a
neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, a neurodegenerative disease associated with neonatal hypoxia-ischemia, or a neurodegenerative disease associated with ischemia during coronary artery bypass grafting.
40. A compound according to claim 39, wherein the neurodegenerative disorder is
Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a
neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, or a neurodegenerative disease associated with neonatal hypoxia-ischemia.
41. Use of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, amide, or ester thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disorder.
42. Use according to claim 41, wherein the neurodegenerative disorder is
Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, familial Creutzfeld-Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, Creutzfeld-Jakob disease, sporadic fatal insomnia, kuru, variant Creutzfeld-Jakob disease, mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, mixed dementia (combination of Alzheimer's disease and vascular dementia), HIV-associated dementia, Lewy body dementia, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, chronic alcoholism, retinitis pigmentosa, deficit in hearing due to degeneration of vestibular and cochlear cells, deficit in balance due to degeneration of vestibular and cochlear cells, a neurodegenerative disease associated with traumatic brain injury, a
neurodegenerative disease associated with spinal cord injury, a
neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, a neurodegenerative disease associated with neonatal hypoxia-ischemia, or a neurodegenerative disease associated with ischemia during coronary artery bypass grafting.
43. Use according to claim 42, wherein the neurodegenerative disorder is
Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a
neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, or a neurodegenerative disease associated with neonatal hypoxia-ischemia.
44. A method for the treatment of a neurodegenerative disorder, which method
comprises administering to a mammal in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, amide, or ester thereof.
45. A method according to claim 44, wherein the neurodegenerative disorder is Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, familial Creutzfeld-Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, Creutzfeld-Jakob disease, sporadic fatal insomnia, kuru, variant Creutzfeld-Jakob disease, mild vascular cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct, vascular dementia due to lacunar lesions, vascular dementia due to hemorrhagic lesions, Binswanger disease, mixed dementia (combination of Alzheimer's disease and vascular dementia), HIV-associated dementia, Lewy body dementia, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, chronic alcoholism, retinitis pigmentosa, deficit in hearing due to degeneration of vestibular and cochlear cells, deficit in balance due to degeneration of vestibular and cochlear cells, a neurodegenerative disease associated with traumatic brain injury, a
neurodegenerative disease associated with spinal cord injury, a
neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, a neurodegenerative disease associated with neonatal hypoxia-ischemia, or a neurodegenerative disease associated with ischemia during coronary artery bypass grafting.
46. A method according to claim 45, wherein the neurodegenerative disorder is
Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, a neurodegenerative disease associated with traumatic brain injury, a neurodegenerative disease associated with spinal cord injury, a
neurodegenerative disease associated with ischemic stroke, a neurodegenerative disease associated with hemorrhagic stroke, or a neurodegenerative disease associated with neonatal hypoxia-ischemia.
47. A pharmaceutical composition comprising as an active ingredient at least one compound according to any one of claims 1 to 36, or a pharmaceutically acceptable ester, amide, or salt thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.
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US11708376B2 (en) 2018-04-20 2023-07-25 Virginia Tech Intellectual Properties, Inc. Substituted imidazo[4,5-b]pyridines, imidazo[4,5-b]pyrazines, and oxazolo[4,5- b]pyrazines as mitochondrial uncouplers
CN110981816A (en) * 2019-12-27 2020-04-10 扬州天和药业有限公司 Synthesis method of 4-amino-2, 6-dimethoxypyrimidine
CN110981816B (en) * 2019-12-27 2022-07-05 天和药业股份有限公司 Synthesis method of 4-amino-2, 6-dimethoxypyrimidine

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