Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods

Definitions

• MPC contains two proteins, MPC1 and MPC2, that form a carrier complex in the inner mitochondrial membrane.
• MPC1 and MPC2 have been identified as components of the mitochondrial target of thiazolidinediones (TZDs). See, e.g. , Colca et al, PLOS ONE 8(5):e 6l55l-e6l55l (2013).
• Pioglitazone is a drug marketed for use in the treatment of diabetes mellitus type 2.
• Pioglitazone is a potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR-g).
• PPAR-g peroxisome proliferator-activated receptor-gamma
• pioglitazone has been associated with unwanted side effects including the potential for drug to drug interactions, cardiovascular effects, fluid retention, weight gain, and bladder cancer (See, e.g., Kus et al. , PLoS ONE 6(11): e27l26 (2011)).
• High doses and/or chronic administration of pioglitazone are therefore undesirable as high systemic exposure would be likely to result in serious side effects.
• the primary mitochondrial disorder is selected from the group consisting of Rett syndrome; dominant optic atrophy (DOA); autosomal dominant optic atrophy (ADOA); Complex I deficiency; Leber hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh’s syndrome; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy with ragged red fibers (MERRF); mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; and chronic progressive external opthalmoplegia (CPEO).
• DOE dominant optic atrophy
• ADOA autosomal dominant optic atrophy
• LHON Leber hereditary optic neuropathy
• KSS Kearns-Sayre syndrome
• MELAS mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
• MELAS myoclonic epilepsy with ragged
• the mitochondrial disease is a secondary mitochondrial disorder selected from the group consisting of selected from the group consisting of Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); myotonic dystrophy (BMD); congenital myopathies; glycogen storage disorders; spinal-bulbar muscular atrophy (SBMA); argininosuccinic aciduria; autism spectrum disorder (ASD); autoimmune diseases of the skin (such as pemphigus vulgaris and lupus); methylmalonic and propionic acidurias; disorders or purine and/or pyrimidine synthesis; facioscapulohumeral muscular dystrophy (FSHD); congenital muscular dystrophies; collagen VI muscular dystrophies (e.g., Ullrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal, and Emery-Dreifuss); DiGeorge syndrome; and neuromuscular disorders (such as limb-girdle muscular dystrophy,
• the method of treatment or prevention comprises administering a mixture of two or more of compounds selected from the group consisting of (2), (3), (4), and (5), or a pharmaceutically acceptable salt thereof, wherein the mixture is optically active.
• compounds (2) and (3) are administered.
• compounds (4) and (5) are administered.
• compounds (2) and (4) are administered.
• compounds (3) and (5) are administered.
• the mitochondrial disease is a secondary mitochondrial disorder selected from the group consisting of selected from the group consisting of Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); myotonic dystrophy (BMD); congenital myopathies; glycogen storage disorders; spinal-bulbar muscular atrophy (SBMA); argininosuccinic aciduria; autism spectrum disorder (ASD); autoimmune diseases of the skin (such as pemphigus vulgaris and lupus); methylmalonic and propionic acidurias; disorders or purine and/or pyrimidine synthesis; facioscapulohumeral muscular dystrophy (FSHD); congenital muscular dystrophies; collagen VI muscular dystrophies (e.g., Ullrich congenital muscular dystrophy, Bethlem myopathy, oculopharyngeal distal, and Emery-Dreifuss); DiGeorge syndrome; and neuromuscular disorders (such as limb-girdle muscular dystrophy,
• FIGURE 2B is a line graph showing the effect of MIN-102 on OCR in A549 cells.
• the patient can be administered a mixture comprising an equimolar amount of each compound (2), (3), (4), and (5), or a pharmaceutically acceptable salt thereof, i.e., each compound in an amount of 25% w/w.
• PK variability or "pharmacokinetic variability” refer to inter-individual variations of a drugs pharmacokinetic parameters, resulting in different plasma concentration-time profiles after administration of the same dose to different patients.
• compositions comprising a Compound of the Disclosure can be administered by any suitable route of administration.
• any of oral, intraoral, topical, epicutaneous, subcutaneous, transdermal, intramuscular, parenteral, ocular, rectal, vaginal, inhalation, buccal, sublingual and intranasal delivery routes can be suitable.
• the present disclosure also relates to the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a mitochondrial disease.
• Oral forms of pharmaceutical compositions can be solid or liquid. Suitable oral dosage forms include tablets, capsules, pills, granules, suspensions, emulsions, syrups or solutions.
• the pharmaceutical compositions may be a solid form selected from, e.g., tablets, capsules, pills, or granules.
• the oral form is a tablet.
• the oral form is an oral solution or suspension.
• Embodiment 18 The method of Embodiment 17, wherein the mixture comprises:
• NAFLD scoring system for liver steatosis, inflammation, fibrosis and hepatocyte ballooning.

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• Health & Medical Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Neurology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Hospice & Palliative Care (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Psychiatry (AREA)
• Ophthalmology & Optometry (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (4)

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• 2019
  • 2019-06-06 FI FIEP19742480.7T patent/FI3801515T3/fi active
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  • 2019-06-06 WO PCT/IB2019/054696 patent/WO2019234664A1/en not_active Ceased
  • 2019-06-06 US US16/972,375 patent/US11957670B2/en active Active
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  • 2019-06-06 EP EP19742480.7A patent/EP3801515B1/en active Active
  • 2019-06-06 JP JP2020567815A patent/JP7376934B2/ja active Active
  • 2019-06-06 DK DK19742480.7T patent/DK3801515T3/da active
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• 2024
  • 2024-04-12 US US18/633,922 patent/US20250064791A1/en active Pending

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