WO2017060420A1 - Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes - Google Patents

Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes Download PDF

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Publication number
WO2017060420A1
WO2017060420A1 PCT/EP2016/073989 EP2016073989W WO2017060420A1 WO 2017060420 A1 WO2017060420 A1 WO 2017060420A1 EP 2016073989 W EP2016073989 W EP 2016073989W WO 2017060420 A1 WO2017060420 A1 WO 2017060420A1
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WIPO (PCT)
Prior art keywords
disease
compound
compound according
compounds
treatment
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PCT/EP2016/073989
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English (en)
Inventor
Steven Moss
Matthew Gregory
Eskil Elmér
Magnus Joakim HANSSON
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Neurovive Pharmaceutical Ab
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Publication of WO2017060420A1 publication Critical patent/WO2017060420A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C07C327/34—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups with amino groups bound to the same hydrocarbon radicals

Definitions

  • the present invention provides novel cell-permeable fumarate acyl
  • the invention also relates to the use of the FAMs in medicine notably in the treatment of multiple sclerosis, psoriasis and non-alcoholic steatohepatitis.
  • Tecfedira is an oral formulation of DMF, which is prescribed for treatment of relapsing remitting multiple sclerosis. Both treatments lead to side effects.
  • FAE therapy include gastrointestinal upset including nausea, vomiting, and diarrhoea;
  • the present invention provides a FAM of Formula (I)
  • At least one of R-i and R 2 is H.
  • the present invention also provides methods for preparing compounds of the invention.
  • the compounds have improved properties for use in medicine.
  • the compounds of the invention are also useful as research tools for mitochondrial in vitro investigations using intact cells or for in vivo animal use.
  • steatohepatitis non-alcoholic fatty liver disease, asthma and chronic obstructive pulmonary diseases, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis and cancer.
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis and cancer.
  • the efficacy of compounds of the invention for treating asthma can be assessed using animal models and in clinical trials.
  • Parkinson's Disease Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease and amyoptrophic lateral sclerosis are characterized by progressive dysfunction and neuronal death.
  • NF- ⁇ inhibition has been proposed as a therapeutic target for neurodegenerative diseases (Camandola and Mattson, Expert Opin Ther Targets 2007, 1 1 (2), 123-32).
  • Alzheimer's disease is a progressive loss of mental function characterized by degeneration of brain tissue, loss of nerve cells and the development of senile plaques and neurofibrillary tangles. Parts of the brain degenerate, destroying nerve cells and reducing the responsiveness of neurons to neurotransmitters. Abnormalities in brain tissue consist of senile or neuritic plaques, containing amyloid and neurofibrillary tangles.
  • Huntington's Disease Huntington's disease is an autosomal dominant neurodegenerative disorder in which cell death occurs in the neostriatum and cortex (Martin, N Engl J Med 1999, 340, 1970- 80). Onset usually occurs during the fourth or fifth decade of life in the 40s or 50s, with a mean survival at age of onset of 14 to 20 years. Huntington's disease is universally fatal, and there is no effective treatment. Symptoms include a characteristic movement disorder (Huntington's chorea), cognitive dysfunction, and psychiatric symptoms. The disease is caused by a mutation encoding an abnormal expansion of CAG-encoded polyglutamine repeats in the protein, huntingtin. The efficacy of compounds of the invention for treating Huntington's disease may be assessed using animal and human models of Huntington's disease and in clinical studies.
  • Friedreich's Ataxia is an ultimately lethal inherited neurodegenerative disease. DMF has shown potential to treat Friedreich's ataxia (Hayashi et al., PLoS One. 2016 Apr 14;1 1 (4):e0153574).
  • Idiopathic Pulmonary Fibrosis (IPF), Scleroderma lung disease, Acute Lung Injury (ALI)/Acute respiratory Distress (ARDS), Chronic Asthma, Radiation-Induced Fibrosis Sarcoidosis, Pulmonary Hypertension, Bronchopulmonary Dysplasia (BPD), Lung Transplant Rejection, Pulmonary GVHD Complications, Interstitial pneumonia Syndrome (IPS) in transplant recipients, COPD, Silicosis, Asbestosis, Sarcoidosis (lung), Primary sclerosing cholangitis (PSC), Alcohol-induced hepatic fibrosis, autoimmune haemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune carditis, Chronic viral hepatitis (HepB/C),
  • Encephalomyopathy Lactic Acidosis; Stroke
  • MERRF Myoclonic Epilepsy; Ragged Red Fibers
  • PEO Progressive External Opthalmoplegia
  • Leigh's Syndrome MNGIE (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-lntestinal;
  • the compound of the invention can also be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
  • HPMC hydroxy-propylcellulose
  • HPC hydroxy-propylcellulose
  • macrogol 8000 sucrose, gelatin and acacia
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g.
  • the compositions are preferably applied as a topical ointment or cream.
  • the active agent When formulated in an ointment, the active agent may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active agent may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • fluid unit dosage forms are prepared utilizing the active ingredient and a sterile vehicle, for example but without limitation water, alcohols, polyols, glycerine and vegetable oils, water being preferred.
  • the active ingredient depending on the vehicle and concentration used, can be either colloidal, suspended or dissolved in the vehicle. In preparing solutions the active ingredient can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • suitable formulations and how to prepare it see eg Remington's Pharmaceutical Sciences 18 Ed. or later).
  • suitable administration route and dosage see eg Remington's Pharmaceutical Sciences 18 Ed. or later.
  • alkene refers to a straight or branched chain composed of carbon and hydrogen atoms wherein at least two carbon atoms are connected by a double bond such as e.g. C 2- io alkenyl unsaturated hydrocarbon chain having from two to ten carbon atoms and at least one double bond.
  • C 2- 6 alkenyl groups include, but are not limited to, vinyl, 1-propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl and the like.
  • the plate is then incubated at 37°C100 ⁇ _ of acetonitrile containing internal standard is added to each the wells after completion of incubation time (0, 15, 30, 60 and 120 minutes) mixed gently, and 50 ⁇ _ of pre-warmed hepatocyte solution added (2 106 cells/mL). At the end of the incubation, cell viability is determined. Samples are centrifuged at 4000 rpm for 15 minutes at 4°C, supernatants diluted 2-fold with ultrapure water and compound levels analysed by LC-MS/MS.
  • solubility in PBS at pH7.4 may be tested as follows: A calibration curve is generated by diluting the test compounds and control compounds to 40 ⁇ , 16 ⁇ , 4 ⁇ , 1 .6 ⁇ , 0.4 ⁇ , 0.16 ⁇ , 0.04 ⁇ and 0.002 ⁇ , with 50% MeOH in ⁇ 20. The standard points are then further diluted 1 :20 in MeOH:PBS 1 :1. The final
  • Potency can be assessed using cell signalling pathway specific cell lines with beta- lactamase (bla) reporter activity (SelectScreen, ThermoFisher).
  • bla beta- lactamase reporter activity
  • a pathway is activated or inhibited beta-lactamase reporter activity is modulated and can be measured quantitatively and selectively.
  • antagonist (inhibitor) mode as is used in the N FKB assay, a serial dilution of test compound or the known inhibitor Withaferin A is added to wells containing cells and medium. The plate is pre-incubated and then the known activator TNF-alpha is added at the pre-determined EC80 concentration. The plate is incubated and then analyzed.
  • HATU 6.2 g, 16.3 mmol
  • the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate. The solvent was evaporated in vacuo and compound 3-2 isolated by column chromatography. TFA (5.8 ml.) was added to a solution of 3-2 (2.9 g, 6.3 mmol) and triethylsilane (1.46 g, 12.6 mmol) in dichloromethane (60 ml.) at 0 °C.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles mercaptoéthylamines de fumarate d'acyle (FAM) à perméabilité cellulaire qui possèdent des effets cellulaires comprenant l'induction de Nrf2 et à l'inhibition de la voie de NFkB. Ces composés sont utiles en médecine, notamment concernant leur utilisation dans le traitement de maladies telles que la sclérose en plaques, la stéatohépatite non alcoolique, le psoriasis, l'arthrite inflammatoire, la maladie inflammatoire chronique de l'intestin, l'asthme, la bronchopneumopathie chronique obstructive, le cancer, la maladie de Parkinson, la maladie d'Alzheimer, la maladie de Huntington et la sclérose latérale amyotrophique.
PCT/EP2016/073989 2015-10-07 2016-10-07 Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes WO2017060420A1 (fr)

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DKPA201570631 2015-10-07
DKPA201570631 2015-10-07

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PCT/EP2016/073989 WO2017060420A1 (fr) 2015-10-07 2016-10-07 Métabolites à base d'acide fumarique protégé destinés au traitement de maladies auto-immunes
PCT/EP2016/073955 WO2017060400A1 (fr) 2015-10-07 2016-10-07 Métabolites protégés à base d'acide carboxylique pour le traitement des maladies liées à des dysfonctions mitochondriales

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US20210346332A1 (en) * 2018-10-11 2021-11-11 Imbria Pharmaceuticals, Inc. Compositions and methods for treating and preventing leber's hereditary optic neuropathy
CN112568868B (zh) * 2020-10-16 2022-12-23 苏州赛美科基因科技有限公司 针对癫痫模型电生理信号的自动量化分析方法及装置

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