WO2011151359A1 - Traitement combiné comprenant un inhibiteur de la cholinestérase et un dérivé de thiadiazolidinedione - Google Patents

Traitement combiné comprenant un inhibiteur de la cholinestérase et un dérivé de thiadiazolidinedione Download PDF

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WO2011151359A1
WO2011151359A1 PCT/EP2011/059007 EP2011059007W WO2011151359A1 WO 2011151359 A1 WO2011151359 A1 WO 2011151359A1 EP 2011059007 W EP2011059007 W EP 2011059007W WO 2011151359 A1 WO2011151359 A1 WO 2011151359A1
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disease
thiadiazolidinedione
derivative
benzyl
substituted
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José María FERNÁNDEZ SOUSA-FARO
Teodoro Del Ser Quijano
Helga CÉSTER SCHLAAK
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Noscira, S.A.
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention is related to a combination of a cholinesterase inhibitor and a thiadiazolidinedione derivative; to a pharmaceutical composition comprising a cholinesterase inhibitor and a thiadiazolidinedione derivative; a medical kit useful for administering in combination a cholinesterase inhibitor and a thiadiazolidinedione derivative; and a method or treatment with a combination of a cholinesterase inhibitor and a thiadiazolidinedione derivative.
  • AD Alzheimer's disease
  • NFTs neurofibrillary tangles
  • ⁇ ⁇ -amyloid
  • APP amyloid precursor protein
  • tau a microtubule-associated protein
  • AD Alzheimer's disease
  • acetylcholinesterase (AChE) inhibition may influence expression of AChE isoforms and increase expression of nicotinic receptors, both of which correlate with cognitive improvements in AD patients.
  • AChE inhibition influences amyloid precursor protein (APP) processing and attenuates ⁇ -induced toxicity via mechanisms including interruption of the production of ⁇ , alteration of the levels of ⁇ 1 -40 and ⁇ 1 -42, and formation of the soluble form of amyloid precursor protein.
  • APP amyloid precursor protein
  • ChEI cholinesterase inhibitors
  • Cholinesterases as used herein comprise AChE and BuChE.
  • cholinesterase inhibitors are marketed worldwide for the treatment of Alzheimer's disease, namely donepezil, galantamine and rivastigmine.
  • compositionula 1 is a reversible inhibitor of acetylcholinesterase (AChE) developed by Eisai for the treatment of Alzheimer's disease (AD).
  • AChE acetylcholinesterase
  • the drug has been launched in over 60 countries worldwide for the once-daily treatment of mild-to-moderate AD, and is approved for the treatment of severe AD in the US.
  • donepezil is marketed for the treatment of vascular dementia.
  • Donepezil is also undergoing late stage clinical development for the treatment of paediatric attention impairment following cancer treatment, dementia associated with Parkinson's disease, Lewy body dementia and for the prevention of migraine.
  • Clinical trials were also initiated for mild cognitive impairment and post-stroke aphasia.
  • Donepezil hydrochloride is available in conventional 5 and 10 mg tablets (o.d.), in rapid disintegration tablet formulations (o.d.), in a 23 mg sustained release tablet formulation (o.d.), in a oral jelly (3, 5 and 10 mg., o.d.) and in an oral liquid solution (5 mg./ml.).
  • Transdermal patch formulations of donepezil are also being developed in the US.
  • the most common adverse events of donepezil defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. See Table 1 for a comparison of the most common adverse events following one and six week titration regimens.
  • Galantamine 1 1 -methyl-6H-benzofuro [3a, 3, 2-ef] [2] benzazepin-6-ol) (formula 2), an alkaloid isolated from the snowdrop Galanthus nivalis, is a highly selective, reversible and competitive inhibitor of acetylcholinesterase.
  • Galantamine has been launched in more than 30 countries for the treatment of mild-to-moderate AD and clinical trials were also started for delirium, mild cognitive impairment, vascular dementia, chronic fatigue syndrome and fibromyalgia.
  • Galantamine hydrobromide is available in conventional tablets (4 mg., 8 mg. and 12 mg. bid), in extended release capsules (8 mg., 16 mg. and 24 mg. o.d.) and in an oral solution formulation (4mg./ml., bid).
  • Galantamine was firstly disclosed in US 4,663,318 and EP 0236684 and, subsequently, it has been included in additional patents, such as US 7,160,559, EP 1 140105, US 6,099,863 or US 6,358,527, US 6,358,941 , US 7,307,162, US 7,297,691 or EP 0449247.
  • additional patents such as US 7,160,559, EP 1 140105, US 6,099,863 or US 6,358,527, US 6,358,941 , US 7,307,162, US 7,297,691 or EP 0449247.
  • the content of the above patent publications is herewith incorporated by specifical reference.
  • Rivastigmine ((S)-N-ethyl-3-[1 -(dimethylamino)ethyl]-N-methyl-phenyl-carbama- te) (formula 3), is a reversible, noncompetitive inhibitor of acetylcholinesterase and butyrylcholinesterase with preferential action at central sites, for the treatment of mild- to-moderately severe AD. Rivastigmine oral capsules were initially approved in Switzerland for AD in 1997, and have since been cleared for marketing in over 70 countries worldwide, including the US, Canada and all of Europe. Furthermore, rivastigmine has been launched for dementia in the UK and is being developed for vascular dementia.
  • Rivastigmine tartrate is available in conventional tablets (1.5 mg., 3 mg., 4.5 mg. and 6 mg., bid), in an oral liquid solution (2 mg./ml.) and in a transdermal patch formulation as a more convenient alternative to the oral capsule formulation.
  • the product is available in two sizes and dosage strengths, i.e. 5 cm 2 (4.6 mg/day) and 10 cm 2 (9.5 mg/day) containing 9 and 18 mg. of rivastigmine, respectively.
  • the rivastigmine transdermal patch is available to date in the US, Canada and the UK, and has been approved in the EU.
  • Rivastigmine was firstly included in US 4,948,807 and EP 0193926.
  • Other patents where rivastigmine is disclosed are US 5,602,176, US 6,316,023, US 6,335,031 , US 6,534,541 , US 6,565,883, US 6,835,748, US 7,531 ,684, US 7,544,840, EP 15291 16, EP 1225890 or EP 1 121 104.
  • the content of the above patent publications is herewith incorporated by specifical reference.
  • AD cholinesterase inhibitors not only clinical and/or preclinical trials for AD have been performed, but also for other disorders or diseases, namely cognitive disorders and neurodegenerative diseases such as dementia, vascular dementia, Huntington's disease, Parkinson's disease or condition, progressive supranuclear palsy, amyotrophic lateral sclerosis, mild cognitive impairment, drug- induced dyskinesia, and other pathologies such as pain, neuropathic pain, myasthenia gravis, poisoning, hypersomnia, smoking withdrawal, HIV infections, inflammatory bowel disease, schistomatosis, urinary incontinence or xerostomia.
  • cognitive disorders and neurodegenerative diseases such as dementia, vascular dementia, Huntington's disease, Parkinson's disease or condition, progressive supranuclear palsy, amyotrophic lateral sclerosis, mild cognitive impairment, drug- induced dyskinesia, and other pathologies such as pain, neuropathic pain, myasthenia gravis, poisoning, hypersomni
  • Additional compounds have been described to inhibit cholinesterases, for example edrophonium, demecarium, ambenonium, neostigmine bromide, dehydroevodiamine chloride, eseroline, imperatorin, scopoletin (SCT), huperizine A (Hup A), heptylstigmine tartrate (MF-201 ), suronacrine maleate (HP-128), UCB-1 1056, berberine iodide, norpyridostigmine, quilostigmine (HP-290, NXX-066), THB-013, PD- 142676, terestigmine tartrate (CHF-2060), thiacymserine, MF-8615, MF-268 bitartrate, anseculin hydrochloride (KA-672.HCI), ensaculin hydrochloride, icopezil maleate (CP- 1 18954), eserine salicylate, physo
  • the first indication for ChEI has been AD. However, with time this indication has been expanded to include other types of dementia and CNS disorders such as dementia [CMAJ, 2008, 179(10), 1019-26. Diagnosis and treatment of dementia: 5. Nonpharmacologic and pharmacologic therapy for mild to moderate dementia. Hogan DB et a/.], vascular & cerebrovascular dementia [Lancet Neurol, 2007, 6, 782-792. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a metaanalysis of randomised controlled trials. Kavirajan H et a/.], frontotemporal dementia [Drugs Aging, 2004, 21(14), 931-7.
  • Rivastigmine in frontotemporal dementia an open-label study. Moretti R et a/.], dementia with Lewy bodies [Dement. Geriatr. Cogn. Disord., 2002, 13, 183-192. Effects of rivastigmine on cognitive function in dementia with Lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system.
  • Glycogen synthase kinase-3 (GSK-3)
  • Glycogen synthase kinase-3 (GSK-3 or GSK3) is a serine/threonine protein kinase comprised of a and ⁇ isoforms that are each encoded by distinct genes [Chemistry & Biology, 2000, 7(10), 793-803. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Coghlan et al.; Curr. Opinion Genetics Dev., 2000, 10(5), 508-514. GSK3, a master switch regulating cell-fate specification and tumorigenesis. Kim, L. & Kimmel, A.R.). GSK-3 plays critical roles in development, metabolic homeostasis, neuronal growth and differentiation, cell polarity, cell fate and in modulation of apoptotic potential.
  • Glycogen synthase kinase-3 GSK3
  • GSK-3 activity is believed to play a role in different and important disorders like neurodegenerative disorders [Physiol. Rev., 2004, 84, 361-84. Role of tau protein in both physiological and pathological conditions. Avila, J. et al.], cardiovascular disease [Circ Res., 2009, 104(11), 1240-52; Role of glycogen synthase kinase-3beta in cardioprotection. Juhaszova M. et al.; Circ J., 2009, 73(7), 1184-92. GSK-3beta, a therapeutic target for cardiomyocyte protection. Miura T. & Miki T], diabetes [Trends. Mol. Med., 2002, 8, 126-32.
  • Glycogen synthase kinase 3 an emerging therapeutic target. Eldar-Finkelman, H.] or viral infections [Virus Res., 2008, 132, 160-73. Residues in human respiratory syncytial virus P protein that are essential for its activity on RNA viral synthesis. Asenjo, A. et al.].
  • GSK-3 deregulation has been related to Alzheimer's disease [Brain Res Bull., 2009, 80(4-5), 248-50.
  • Glycogen synthase kinase- 3beta is associated with Parkinson's disease. Masahiro N. & Hideaki H.], frontotemporal dementia [Arch. Neurol., 2008, 65, 1368-74. Association of GSK3B with Alzheimer disease and frontotemporal dementia.. Schaffer, B.
  • Glycogen synthase kinase 3 beta (GSK- 3 beta) as a therapeutic target in neuroAIDS. Dewhurst S. et al.], Huntington's disease [J Biol Chem., 2002, 277(37), 33791-8. Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. Carmichael J. et al.], Lewy body disease [Neuropathology., 2003, 23(3), 199-202.
  • Glycogen synthase kinase-3beta phosphorylates synphilin-1 in vitro.
  • Tanji K. et al. bipolar disorder [Neurosci Biobehav Rev., 2007, 31(6), 920-931; GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder.
  • Glycogen Synthase Kinase ⁇ mood stabilizers, and neuroprotection. Li X. et al.] , depression [J Pharmacol Sci., 2009, 110(1), 14-28.
  • Lithium and neuropsychiatric therapeutics neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades. Wada A.], schizophrenia [Drug News Perspect., 2007, 20(7), 437-45. The role of glycogen synthase kinase-3beta in schizophrenia. Koros E. & Dorner-Ciossek C; Trends Neurosci., 2007, 30(4), 142-9. Schizophrenia as a GSK-3 dysregulation disorder. Lovestone S. et al.], epilepsy [J Neurochem., 1999, 72(3), 1327-30.
  • the mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. Chen G. et al.], mood disorders [Curr Drug Targets., 2006, 7(11), 1421-34. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Jope R.S. & Roh M.S.], autism [Proc Natl Acad Sci U S A., 2008, 105(4), 1333-8. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Beaulieu J.M. et al.], attention deficit hyperactivity disorder [Proc Natl Acad Sci U S A., 2004, 101(14), 5099-104.
  • glycogen synthase kinase-3beta Different expression of glycogen synthase kinase-3beta between young and old rat brains after transient middle cerebral artery occlusion.
  • Sasaki C. et a/. multiple sclerosis [Trends Immunol., 2010, 31(1), 24-31.
  • GSK3 glycogen synthase kinase-3
  • Beurel E. et a/. and other autoimmune and inflammatory diseases afflicting the CNS [J. Immunol., 2008, 181(1), 338-45. Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. De Sarno P.
  • amyotrophic lateral sclerosis or amyotrophic lateral sclerosis [Brain Res., 2008, 1196, 131-139. Upregulation of GS 3/3 expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). Yang W. et a/.].
  • GSK3 inhibitors may also be useful to foster other forms of neuronal repair, including axon regeneration [J. Neurosci., 2008, 28, 8914-28. Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. Dill, J. et a/.].
  • GSK-3 has been identified as a regulator of many components of the immune system, suggesting it might be a plausible therapeutic target in inflammatory and autoimmune diseases, such as chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis [Eur J Biochem., 2001, 268(19), 5001-10.
  • chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis
  • arthritis [Clin. Immunol., 2006, 120, 57-67.
  • Glycogen synthase kinase-3b inhibition attenuates the degree of arthritis caused by type II collagen in the mouse. Cuzzocrea, S.
  • IFN-g suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins.
  • Hu, X. et a/.] systemic inflammation, renal dysfunction and hepatotoxicity in endotoxemia [Crit. Care Med., 2005, 33, 1903-1912.
  • GSK-3b inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat.
  • Dugo, L. et a/. asthma [Am J Physiol Lung Cell Mol Physiol., 2009, 296(2), L176-84.
  • GSK-3b inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone treated myotubes. Int. Evenson, A.R. et a/.], colitis [Br. J. Pharmacol., 2006, 147, 575-582. Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3b. Whittle, B.J.
  • Glycogen synthase kinase-3beta a novel regulator of cardiac hypertrophy and development. Hardt, S.E. & Sadoshima, J.], atherosclerosis [Am J Pathol., 2009, 174(1), 330-42. Valproate attenuates accelerated atherosclerosis in hyperglycemic apoE-deficient mice: evidence in support of a role for endoplasmic reticulum stress and glycogen synthase kinase-3 in lesion development and hepatic steatosis. Bowes A.J. et a/.], hypertension [J.
  • Fas receptor signaling inhibits glycogen synthase kinase 3 ⁇ and induces cardiac hypertrophy following pressure overload. Badorff C. et a/.], restenosis [Cardiovasc Res., 2010, Epub. Delayed Re-endothelialization with Rapamycin-coated Stents is Rescued by the Addition of a Glycogen Synthase Kinase 3 Beta Inhibitor. Ma X. et a/.] or leukopenia [Gallicchio, V. S. (1991) in Lithium and the Cell, ed. Birch, N. J. (Academic, San Diego), pp. 185-198.].
  • GSK-3 Additional pathologies associated with GSK-3 are metabolic syndrome X [Curr Pharm Des., 2004, 10(10), 1105-37. Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes. Wagman A.S. et a/.], hair loss [J Clin Invest., 2010, 120(2), 446-56. Neural Wiskott-Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice. Lyubimova A. et a/.], severe acute respiratory syndrome coronavirus [J Biol Chem., 2009, 284(8), 5229-39.
  • Glycogen synthase kinase-3 regulates the phosphorylation of severe acute respiratory syndrome coronavirus nucleocapsid protein and viral replication. Wu C.H. et a/.], cocaine addiction [J Neurochem., 2009, 111(6), 1357-68. Glycogen synthase kinase 3beta in the nucleus accumbens core mediates cocaine-induced behavioral sensitization. Xu CM. et a/.], bone loss [Life Sci., 2009, 85(19-20), 685-92. Inhibition of glycogen synthase kinase-3beta attenuates glucocorticoid-induced bone loss. Wang F.S.
  • GSK-3 inhibitors development end therapeutic potential. Cohen, P. & Goedert, M.; Mini- Reviews in Medicinal Chemistry, 2009, 9(9), 1024-1029. GSK3 Inhibitors and Disease. Hernandez, F. et al.; Curr. Opin. Drug Discov. Develop., 2008, 1 1 (4), 533-543.
  • Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic. Medina, M. & Castro, A.; John Wiley & Sons, Inc., 2006. Glycogen Synthase Kinase 3 (GSK-3) and its inhibitors. Chapter 14. Eds: Martinez, A., Castro, A. & Medina, M.
  • Thiadiazolidinediones Small heterocyclic thiadiazolidinediones, the first ATP non-competitive GSK-3 inhibitors reported to date, have been proposed as new disease-modifying agents for the effective treatment of Alzheimer's d isease and other pathologies. These compounds have great interest since they may be disease modifying agents in AD.
  • the present invention provides a combination of at least one thiadiazolidinedione derivative of formula (I) and a therapeutically effective amount of at least one cholinesterase inhibitor, o r a pharmaceutically acceptable salt or solvate thereof, wherein the cholinesterase inhibitor may form part of a separate medicament or the same medicament, and wherein formula (I) is:
  • n zero, one or two;
  • t is zero, one, two or three;
  • the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one thiadiazolidinedione derivative of formula (I) as defined above or a pharmaceutically acceptable salt or solvate thereof, a therapeutically effective amount of a cholinesterase inhibitor or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutical carrier, adjuvant and/or vehicle.
  • a medical kit comprising
  • An additional aspect of the present invention is a thiadiazolidinedione derivative of formula (I) as defined above, for use in the reduction of side effects caused by the treatment with a cholinesterase inhibitor.
  • An additional aspect of the present invention is a combination or a composition or a kit for use as a medicament.
  • the present invention refers to the use of at least one thiadiazolidinedione derivative of formula (I) as defined above, in the preparation of a medicament for the treatment of a human patient affected by a cholinesterase or GSK-3 mediated disease by combination therapy, involving the administration of a therapeutically effective amount of at least one thiadiazolidinedione derivative if formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of at least one cholinesterase inhibitor or a pharmaceutically acceptable salt or solvate thereof, wherein the cholinesterase inhibitor may form part of a separate medicament or the same medicament.
  • a further aspect of the present invention is a method of treating a GSK3 or cholinesterase mediated disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a thiadiazolidinedione derivative of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of a cholinesterase inhibitor, o r a pharmaceutically acceptable salt or solvate thereof.
  • Figure 1 is a graphical representation of the evolution of MMSE (Mini Mental State Examination) score from baseline to the end of the study, split by placebo and active in those patients who were escalated up to 1 ,000 mg of thiadiazolidine derivative once daily, and thus completed the study.
  • MMSE Minimum Mental State Examination
  • Figure 2 is a graphical representation of the evolution of Alzheimer's Disease assessment Scale (ADAS-cog+) score, from baseline to the end of the study, split by placebo and active in those patients who were escalated up to 1 ,000 m g of thiadiazolidine derivative once daily, and thus completed the study.
  • ADAS-cog+ Alzheimer's Disease assessment Scale
  • Figure 3 is a graphical representation of the Global Clinical Assessment of changes observed at the end of the study, split by placebo and active
  • Figure 4 is a table detailing the incidence of adverse effects (absolute number and percentage) during the study, classified by Organ-System Class, split by placebo and active.
  • GSK3 or cholinesterase mediated disease refers to any disease or condition wherein a modulation of the expression or activity of GSK3 or cholinesterase may be of benefit for patients suffering said disease or condition. This includes, but is not limited to, those diseases or conditions implying a deregulation in the expression or activity of GSK3 or cholinesterase.
  • carrier, adjuvant and/or vehicle refers to molecular entities or substances with which the active ingredients are administered.
  • Such pharmaceutical carriers, adjuvants or vehicles can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, excipients, disgregants, wetting agents or diluents.
  • Suitable pharmaceutical carriers, adjuvants and/or vehicles are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • C1 -C6 Alkyl refers to a straight or branched hydrocarbon chain radical, said chain consisting of 1 to 6 carbon and hydrogen atoms, preferably, 1 to 3 carbon atoms, containing no saturation, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
  • Alkyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
  • alkenyl means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein, said chain consisting of 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl,4-(2-methyl-3-butene)- pentenyl.
  • An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
  • Alkoxy refers to a radical of the formula -OR z where R z is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • Aryl refers to an aromatic ring system. According to one embodiment, aryl groups comprise 6 to 14 carbon atoms, more particularly 6 to 10, even more particularly 6 carbon atoms. According to an embodiment, aryl is a phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical, preferably phenyl or naphthyl radical. Said aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined herein.
  • Benzo-fused heterocyclic ring system refers to a phenyl ring, fused to one or two further rings, at least one of them being a heterocycle or heteroaryl, especially an oxygen containing heterocycle or heteroaryl, e.g. benzo[1 ,3]dioxol, benzoimidazol, benzofurane, etc.
  • Cycloalkyl refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, preferably, 3 to 8 carbon atoms, more preferably 5, 6 or 7 carbon atoms. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.
  • Halo refers to bromo, chloro, iodo or fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e. g., trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1 -fluoromethyl-2-fluoroethyl, and the like.
  • heteroaryl means a monocyclic- or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • the heteroayl group has 3 to 15 members. In a particular embodiment it has 4 to 8 members.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1 ,2,3,)- and (1 ,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl, isoxazolyl, and oxazolyl.
  • a heteroaryl group can be unsubstituted or substituted with one or two suitable substituents.
  • a heteroaryl group is a monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms ".
  • Heterocycle refers to a heterocyclyl radical.
  • the heterocycle refers to a stable
  • the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic.
  • heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.
  • references herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1 -6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1 -3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether
  • the efficacy of the cholinesterase inhibitor in the treatment of the corresponding disease is improved by co-administering the thiadiazolidinedione derivative. Therefore, the combined treatment with a cholinesterase inhibitor and a thiadiazolidinedione derivative shows important advantages with respect to the treatment with cholinesterase inhibitors alone, increasing the efficacy of the cholinesterase inhibitor treatment, and reducing the adverse effects, in most System- Organ Classes.
  • composition comprising a therapeutically effective amount of at least one thiadiazolidinedione derivative of formula (I) a therapeutically effective amount of a cholinesterase inhibitor, and at least one pharmaceutical carrier, adjuvant and/or vehicle;
  • a medical kit comprising (i) a supply of thiadiazolidinedione derivative of formula (I) and a pharmaceutically acceptable carrier, adjuvant and/or veh icle, and (ii) instructions for administering the thiadiazolidinedione derivative in combination with a cholinesterase inhibitor;
  • a thiadiazolidinedione derivative as defined above for use in the reduction of side effects caused by the treatment with a cholinesterase inhibition;
  • a method of treating a GSK3 or cholinesterase mediated disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a thiadiazolidinedione derivative of formula (I) and a therapeutically effective amount of a cholinesterase inhibitor.
  • the thiadiazolidinedione derivative has formula (II): wherein:
  • R a is an organic group comprising at least one aromatic ring and having at least 8 atoms selected from C or O;
  • t is zero, one, two or three
  • R 7 a n d R 8 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, halogen;
  • the thiadiazolidinedione derivative is 4-benzyl-2-naphtalen-1 -yl-
  • the above defined aspects may either comprise one thiadiazolidinedione derivative or a pharmaceutically acceptable salt or solvate thereof, or more than one of such thiadiazolidinedione derivatives.
  • the above defined aspects may either comprise one cholinesterase inhibitor or a pharmaceutically acceptable salt, or more than one such cholinesterase inhibitors.
  • the above aspects comprise one thiadiazolidinedione derivative and one cholinesterase inhibitor.
  • the above aspects may comprise, additionally to the thiadiazolidinedione derivative and the cholinesterase inhibitor, other pharmaceutically active compounds.
  • the cholinesterase inhibitor derivative is selected from the group consisting of Donepezil, Galantamine, Rivastigmine, tacrine hydrochloride, huperzine A, acotiamide, dimebolin, DEBIO 9902, EN 101 , phenserine tartrate, R-phenserine, stacofylline hydrochloride (S-9977, S-9977- 2), NP-61 , bisnorcymserine, COL-204, SPH 1371 , SPH 1373, SPH 1375, SP 04, CM 2433, metrifonate, 7-methoxytacrine (7 MEOTA), P 1 1 149, Arisugacin, FR 152558, H U P 1 3 , isovan ih uperzine A (IVHA), M H P 1 33 , N P 7557, P 1 0358 , P 1 1 01 2 , physostigmine salicylate,
  • HCI ensaculin hydrochloride
  • icopezil maleate CP- 118954
  • eserine salicylate physostigmine salicylate
  • JWS-USC-75IX P11467, P-10358
  • bis(7)-tacrine HMR- 2420, CP-126998, TV-3279, MSF, THA-C8, subergorgic acid, suberogorgin, SPH- 1286, huperzine B (Hup B), pyridostigmine bromide (Ro-1-5130), huprine Y, coronaridine, RS-1233, kobophenol A, bis(12)-huperine, RS-1259, ITH-4012, TK-19, T- 81, TH-171, TH-185, distigmine bromide (BC-51), (-)-9-dehydrogalanthaminium bromide, memoquin, scopoletin 7-O-beta-D- glucopyran
  • the cholinesterase inhibitor is selected from the group consisting of Donepezil, Galantamine and Rivastigmine.
  • the cholinesterase inhibitor and the thiadiazolidinedione derivative form part of the same medicament.
  • the cholinesterase inhibitor and the thiadiazolidinedione derivative are administered as separate medicaments.
  • the separate medicament comprising the cholinesterase inhibitor may be administered at the same time as the medicament comprising the thiadiazolidinedione derivative.
  • the separate medicament comprising the cholinesterase inhibitor may be administered at a different time than the medicament comprising the thiadiazolidinedione derivative.
  • the GSK-3 mediated disease to be treated is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Pick's disease, progressive supranuclear palsy, subacute panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, corticobasal degeneration, argyrophilic grain disease, familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau), AIDS associated dementia, Huntington's disease, Lewy body disease, bipolar disorder, depression, schizophrenia, epilepsy, mood disorders, autism, attention deficit hyperactivity disorder, Down's syndrome, ischemia/reperfusion and shock, brain injury, multiple sclerosis, autoimmune and inflammatory diseases afflicting the CNS, spinocerebellar ataxia type 1 , cerebral bleeding due to solitary cerebral amyloid angiopathy, amy
  • the cholinesterase mediated disease is selected from cognitive disorders and neurodegenerative diseases, dementia, vascular dementia, Huntington's disease, Parkinson's disease or condition, progressive supranuclear palsy, amyotroph ic lateral sclerosis, m ild cogn itive impairment, drug-induced dyskinesia, and other pathologies such as pain, neuropathic pain, nociceptive pain, myasthenia gravis, poisoning, hypersomnia, smoking withdrawal, HIV infections, inflammatory bowel disease, schistomatosis, urinary incontinence, xerostomia, cerebrovascular dementia, frontotemporal dementia, dementia with Lewy bodies, dementia with argyrophilic grains (AG), essential tremor and tardive dyskinesia, prion disease, attention deficit hyperactivity disorder (ADHD), Down syndrome, traumatic brain injury, migraine, systemic amyloidosis or condition, ataxia, cognitive impairment in multiple sclerosis, narcolepsy, hyperkinesis
  • ADHD
  • the disease to be treated is selected from Alzheimer's disease, Parkinson's disease or condition , dementia, vascular dementia, cerebrovascular dementia, dementia with Lewy bodies, dementia with argyrophilic grains (AG), frontotemporal dementia, Pick's disease, progressive su pran uclear palsy, subacute panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, corticobasal degeneration, argyrophilic grain disease, familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP- 17-tau), AIDS associated dementia, Huntington's disease, Lewy body disease, bipolar disorder, depression, schizophrenia, epilepsy, mood disorders, autism, attention deficit hyperactivity disorder, Down's syndrome, ischemia/reperfusion and shock, brain injury, traumatic brain injury, multiple sclerosis, autoimmune and inflammatory dementia, Alzheimer's disease, Parkinson
  • the disease is selected from
  • the effective amount of thiadiazolidine derivative is comprised between 400 and 1 ,000 mg, preferably between 400 and 800 mg/day, more preferably between 400 and 600 mg.
  • the therapeutically effective amount of cholinesterase derivative is the amount thereof commonly prescribed, preferably the minimum dose or even below, as efficacy is improved by the combination according to the present application.
  • the therapeutically effective amount thereof is comprised between 3 and 10 mg/day, preferably between 3 and 5 mg, more preferably is 3 mg.
  • the amount may also be comprised between 1 and 3 mg/day.
  • the effective amount is comprised between 4 and 24 mg, preferably between 4 and 16 mg, more preferably between 4 and 12 mg, even more preferably between 4 and 8 mg. The amount may also be comprised between 1 and 4 mg/day.
  • the effective amount is comprised between 1 .5 and 12 mg/day, preferably between 1 .5 and 9.5 mg, more preferably between 1.5 and 6 mg, even more preferably between 1 .5 and 4.6 mg, and most preferably between 1 .5 and 3 mg.
  • the effective amount of at least one thiadiazolidinedione derivative or a pharmaceutically acceptable salt or solvate thereof and the effective amount of a cholinesterase inhibitor may be administered by oral administration, subcutaneous administration, including subcutaneous implants and injections, by intravenous administration, cutaneous administration (e.g. patches), intramuscular administration, intraperitoneal, sublingual or by nasal administration.
  • both drugs When the effective amounts of the thiadiazolidinedione derivative and the cholinesterase inhibitor are comprised in the same medicament, the administration of both drugs will evidently be performed by the same route, which may be selected from the above detailed administration routes.
  • both drugs may be administered as an oral medicament; or both drugs may be administered as a subcutaneous medicament; etc.
  • the administration of each of them may be performed by the same or by different routes, which may be selected from the above detailed administration routes.
  • both the medicament comprising the thiadiazolidinedione derivative and the medicament comprising the cholinesterase inhibitor may be administered orally.
  • the medicament comprising the thiadiazolidinedione derivative may be administered orally, while the medicament comprising the cholinesterase inhibitor is administered subcutaneously; etc. All possible combinations of routes of administration of the both medicaments and drugs are meant to be comprised within the present invention.
  • said medical kit further comprises (iii) a supply of a cholinesterase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • the patients were administered either escalating doses from 400 mg to 1 ,000 mg during 20 weeks, once daily, of said thiadiazolidinedione derivative ("Active” group), o r a matching placebo ("Placebo" group). That is, patients in the Placebo group received cholinesterase inhibitor treatment and a placebo, and patients in the Active group received cholinesterase inhibitor treatment and thiadiazolidinedione derivative treatment. Particularly, 20 patients were treated with Active, and another 10 patients with Placebo. All the patients had been diagnosed of mild to moderate Alzheimer's Disease; they were aged in the range of 55 to 84 years; 20 were women and 10 were men.
  • efficacy endpoints related to the assessment of cognition and global functioning were monitored at baseline and regularly throughout the study.
  • Global Clinical Assessment was performed at the end of the double-blind period.
  • MMSE Mini-Mental State Examination
  • the MMSE is a frequently used screening instrument for AD drug studies. It evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, ability to create a sentence and ability to copy two intersecting polygons. A lower score indicates greater cognitive impairment. The highest possible (best) score is 30. For further detail, see for example J. Psychiatr. Res. 1975, 12, 189, which is herewith incorporated by reference.
  • ADAS-cog+ a composite questionnaire assessing memory, language, praxis functions, delayed word recall, concentration distractibility, digit cancellation and maze completion.
  • the total score is calculated from the ADAS-cog+ sub scale scores and ranges from 0 (No impairment) to 95 (Errors in all sub-tests). Therefore, higher scores are associated with greater cognitive impairment.
  • ADAS-cog+ a composite questionnaire assessing memory, language, praxis functions, delayed word recall, concentration distractibility, digit cancellation and maze completion.
  • the total score is calculated from the ADAS-cog+ sub scale scores and ranges from 0 (No impairment) to 95 (Errors in all sub-tests). Therefore, higher scores are associated with greater cognitive impairment.
  • Alzheimer Dis Assoc Disord. 2004, 18(4), 236-40 which is herewith incorporated by reference.
  • the investigator evaluated the overall clinical state of the patients, in comparison with their basal state at the start of the study, in a seven point scale: markedly better, much better, slightly better, similar, slightly worse, much worse, markedly worse.
  • Figure 1 the mean change in MMSE score from baseline (considered "0"), in absolute figures, for both Placebo and Active groups, are shown.
  • the patients being administered Placebo showed a decline in the MMSE score during the 20 weeks, specifically by a mean value of 1.13 points in the MMSE scale, according to the expected rate of around 2.5 points per year. That means, their neurodegenerative disease continued worsening during the study.
  • Placebo and Active was determined several times along the phase lla study (baseline, week 4, week 8, week 14 and week 20).
  • the patients being administered Active not only did not worsen their state, maintaining the same MMSE score, but even experienced an improvement with respect to the baseline value, specifically a mean reduction of 1 .60 points in the ADAS- cog+ score.
  • a clear improvement in the ADAS-cog+ score was detected in the patients receiving concurrently a cholinesterase inhibitor treatment and Active, in comparison with those being treated with a cholinesterase inhibitor and Placebo; i.e., the combined treatment of a cholinesterase inhibitor and the thiadiazolidinedione derivative has shown clearly more effective than the treatment with cholinesterase inhibitor alone, despite the Phase lla study being a relatively short study, which was initially designed for proving safety and tolerability of the Active, and not for determining efficacy of the Active.
  • Cardiac disorders Particularly, the following particular adverse events were classified within the above classes: Cardiac disorders:
  • the adverse events were higher in the Placebo group (being administered only cholinesterase inhibitors) than in the Active group (being administered both cholinesterase inhibitors and the thiadiazolidinedione derivative). Especially unexpected is the reduction in gastrointestinal adverse effects, which are typical and frequent side effects of the treatment with cholinesterase inhibitors. The results suggest that the adverse effects occu rri ng d u ring the treatment with cholinesterase inhibitors are reduced by co-administering the Compound, without significantly adding other adverse effects.

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Abstract

La présente invention concerne une combinaison d'un inhibiteur de la cholinestérase et d'un dérivé de thiadiazolidinedione ; une composition pharmaceutique comprenant un inhibiteur de la cholinestérase et un dérivé de thiadiazolidinedione ; un kit médical utile pour l'administration en combinaison d'un inhibiteur de la cholinestérase et d'un dérivé de thiadiazolidinedione ; un procédé ou un traitement avec une combinaison d'un inhibiteur de la cholinestérase et d'un dérivé de thiadiazolidinedione.
PCT/EP2011/059007 2010-06-02 2011-06-01 Traitement combiné comprenant un inhibiteur de la cholinestérase et un dérivé de thiadiazolidinedione WO2011151359A1 (fr)

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WO2015006643A3 (fr) * 2013-07-12 2015-11-05 Immuneering Corporation Systèmes, procédés, et environnement pour l'examen automatisé de données génomiques pour identifier une expression génétique régulée à la baisse et/ou régulée à la hausse indicative d'une maladie ou d'un état
JP7074808B2 (ja) 2014-07-17 2022-05-24 アンセルム 神経筋接合部関連疾患の処置方法
JP2020183431A (ja) * 2014-07-17 2020-11-12 アンセルムＩｎｓｅｒｍ 神経筋接合部関連疾患の処置方法
US10202443B2 (en) 2014-12-05 2019-02-12 UNIVERSITé LAVAL TDP-43-binding polypeptides useful for the treatment of neurodegenerative diseases
JP2018516901A (ja) * 2015-05-18 2018-06-28 シナプテック・ディヴェロップメント・エルエルシーＳｙｎａｐｔｅｃ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｌｃ アミロイドβのガランタミンクリアランス
CN105998045A (zh) * 2016-06-27 2016-10-12 王双喜 治疗动脉粥样硬化的药物组合物及其应用
CN109200051A (zh) * 2017-07-03 2019-01-15 南京和博生物医药有限公司 石杉碱甲及其类似物作为治疗炎症性疾病药物的用途
CN110251507A (zh) * 2019-07-04 2019-09-20 西安交通大学 一种针对p物质引发的哮喘的药物应用
WO2022100570A1 (fr) * 2020-11-12 2022-05-19 科辉智药生物科技(深圳)有限公司 Inhibiteur de l'activité de l'enzyme sarm1 et son utilisation dans des maladies neurodégénératives
CN115197167A (zh) * 2022-07-22 2022-10-18 中国药科大学 1,2,4-噻二唑烷-3,5-二酮化合物及其制备方法和应用
CN115197167B (zh) * 2022-07-22 2023-07-28 中国药科大学 1,2,4-噻二唑烷-3,5-二酮化合物及其制备方法和应用
CN117298098A (zh) * 2023-11-15 2023-12-29 南通大学 氧化前胡素在制备治疗血管性痴呆药物中的应用

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