WO2011151359A1

WO2011151359A1 - Combined treatment with a cholinesterase inhibitor and a thiadiazolidinedione derivative

Info

Publication number: WO2011151359A1
Application number: PCT/EP2011/059007
Authority: WO
Inventors: José María FERNÁNDEZ SOUSA-FARO; Teodoro Del Ser Quijano; Helga CÉSTER SCHLAAK
Original assignee: Noscira, S.A.
Priority date: 2010-06-02
Filing date: 2011-06-01
Publication date: 2011-12-08

Abstract

A combination of a cholinesterase inhibitor and a thiadiazolidinedione derivative; 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; a method or treatment with a combination of a cholinesterase inhibitor and a thiadiazolidinedione derivative.

Description

COMBINED TREATMENT WITH A CHOLINESTERASE INHIBITOR AND A

THIADIAZOLIDINEDIONE DERIVATIVE

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized clinically by memory and cognitive dysfunction. The neuropathology of AD is characterized by two types of lesions, senile plaques and neurofibrillary tangles (NFTs), composed respectively of β-amyloid (Αβ), a cleavage product of the amyloid precursor protein (APP), and aberrantly phosphorylated tau, a microtubule-associated protein (for a review of AD pathology, see J Clin Invest., 1999, 104(9), 1169-70. Alzheimer's disease: perspectives for the new millennium. Sisodia S.S.; Physiol Rev, 2001, 81, 741-766. Alzheimer's disease: genes, proteins, and therapyphysiology. Selkoe D.J.; Alzheimer Disease & Associated Disorders, 2003, 17(4), 259-266. Molecular and Cellular Basis for Anti-Amyloid Therapy in Alzheimer Disease. Gandy, S. et al.; Nat Rev Neurosci., 2007, 8(9), 663-72. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Ballatore, C. et al.)

Although sporadic AD is rare in individuals younger than 60 years of age, the incidence steadily increases with age, affecting up to 40% of those who are more than 85 years old. In 2006, there were more than 26 million cases of AD in the world and it is expected that by the year 2050 the worldwide prevalence of AD will grow fourfold to almost 107 million [Alzheimer's & Dementia, 2007, 3(3), 186-191. Forecasting the global burden of Alzheimer's disease. Brookmeyer, R. et al.].

Cholinesterase inhibition as a treatment of AD

There is evidence from preclinical studies, and some studies in humans, that cholinesterase inhibition affects basic processes that have been implicated in AD pathogenesis. For example, 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. It has also been shown that AChE inhibition influences amyloid precursor protein (APP) processing and attenuates Αβ-induced toxicity via mechanisms including interruption of the production of Αβ, alteration of the levels of Αβ1 -40 and Αβ1 -42, and formation of the soluble form of amyloid precursor protein.

Therefore currently, cholinesterase inhibitors (ChEI) represent the treatment of choice for Alzheimer's disease (AD) therapy. Following the introduction in the late eighties of a first generation of drugs, represented by physostigmine and tacrine, a second generation of more suitable compounds were developed in the nineties. Three of them have reached the market: donepezil, rivastigmine and galantamine. The symptomatic effects of ChEls (due to increases in cholinergic neurotransmission) have been demonstrated in a number of large, randomized controlled trials.

The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are involved in the breakdown of acetylcholine in the brain and inhibition of these enzymes may produce symptomatic effects in numerous pathologies [CNS Drugs, 1999, 12(4), 307-23. Selectivity of cholinesterase inhibition. Clinical implications for the treatment of Alzheimer's disease. Weinstock, M.]. Hence, Cholinesterases as used herein comprise AChE and BuChE.

Marketed Cholinesterase Inhibitors

Currently, three cholinesterase inhibitors are marketed worldwide for the treatment of Alzheimer's disease, namely donepezil, galantamine and rivastigmine.

Donepezil (1 -Benzyl-4-[(5,6-dimethoxy-1 -indanon)-2-yl]-methyl-piperidine)

(formula 1 ) is a reversible inhibitor of acetylcholinesterase (AChE) developed by Eisai for the treatment of Alzheimer's disease (AD). 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. Additionally, 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.

Formula 1

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.

Table 1.- Comparison of rates of adverse events in patients titrated to 10 mg/day over 1 and 6 weeks

The adverse events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Results regarding adverse events reported in controlled clinical trials in at least 2% of patients receiving donepezil (Aricept^®) and at a higher frequency than placebo-treated patients, confirm that the most common adverse events related with donepezil are gastrointestinal disorders, i.e. nausea (1 1 % vs. 6%) and diarrhea (10% vs. 5%) [for additional information in connection with adverse events, see "Physicians' Desk Reference. Ed. Thomson PDR. 60^th edition. 2006"; herewith incorporated by specifical reference].

Donepezil was disclosed for the first time in example 4 of US 4,895,841 and EP

296560. Subsequently, donepezil has been included in numerous patents, such as US 5,985,864, US 6,140,321 , EP 1019374, EP 121 1243, US 6,245,91 1 , EP 1048653, US 6,252,081 , US 6,372,760, EP 1086706, US 6,252,081 , US 6,458,807, US 6,492,522, US 6,576,646, US 6,576,677, US 6,608,088, US 6,649,765, US 6,689,795, US 6,734,195, US 6,844,440, US 6,953,856, US 7,148,354, US 7,186,842, US 7,446,203, US 7,563,808, US 7,592,459, EP 1531 151 , EP 1513528, EP 1386607, EP 1323712, EP 0947193 or EP 1047674. The content of the above patent publications is herewith incorporated by specifical reference. Galantamine ([4aS-(4aa, 6β, 8aR^*)]-4a, 5, 9, 10, 1 1 , 12-Hexahydro-3-methoxy-

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.

Formula 2 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).

The most frequent adverse events of galantamine, defined as those occurring at a freq u en cy of at least 5% a nd at least twi ce th e rate on pl acebo with the recommended maintenance dose of either 16 or 24 mg/day of galantamine (Razadyne^®) under condition s of eve ry 4-week dose-escalation for each dose increment of 8 mg/day, are shown in table 2.

Table 2.- Most frequent adverse events of galantamine.

The most common adverse events (adverse events occurring with an incidence of at least 2% with galantamine (Razadyne^®) treatment and in which the incidence was greater than with placebo treatment) for four placebo-controlled trials for patients treated with 1 6 or 24 mg/day of galantamine (Razadyne^®) were confirmed to be gastrointestinal disorders, i.e. nausea (24% vs. 9%) and vomiting (13% vs. 4%) [for additional information in connection with adverse events, see "Physicians' Desk Reference. Ed. Thomson PDR. 60^th edition. 2006"; herewith incorporated by specifical reference].

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. 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.

CH

Formula 3

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 cm² (4.6 mg/day) and 10 cm² (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.

The most common adverse events, defined as those occurring at a frequency of at least 5% and twice the placebo rate, are significant gastrointestinal events including nausea, vomiting, anorexia and weight loss. Furthermore, table 3 lists treatment emergent signs and symptoms that were reported in placebo-controlled clinical trials in at least 2% of patients and for which the rate of occurrence was greater for patients receiving rivastigmine (Exelon^®) (6-12 mg/day) than for those treated with placebo, [for additional information in connection with adverse events, see "Physicians' Desk Reference. Ed. Thomson PDR. 60^th edition. 2006"; herewith incorporated by specific reference]. Table 3.- Most frequent adverse events of rivastigmine.

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.

Other cholinesterase inhibitors in clinical or preclinical development

Clinical and/or preclinical trials have also been performed for other cholinesterase inhibitors, namely for tacrine hydrochloride (CI-970, THA.HCI), 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, HUP 13, isovanihuperzine A (IVHA), MHP 133, NP 7557, P 10358, P 1 1012, physostigmine salicylate, velnacrine maleate (HP- 029, P83-6029A), epastigmine tartrate (L-693487), ipidacrine, zanapezil, ganstigmine, icopezil maleate (CP-1 18954, CP-1 18954-1 1 ), KW 5092, quilostigmine (HP-290, NXX- 066), SM 10888, T 82, TAK 802, zifrosilone MDL-73745), BGC 201259, CHF 2060, CI 1002, E 2030, ER 127528, ET 142, F 3796, huprine X, MF 247, MF 268 bitartrate, MF 8615, P 26, PD 142012, RO 465934, SS 20, thiatolserine, tolserine tartrate, UR 1827. (Source: ADIS R&D Insight, on 25/02/2010; herewith incorporated by specifical reference) For the above indicated 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. (Source: ADIS R&D Insight, on 25/02/2010; herewith incorporated by specifical reference)

Other cholinesterase inhibitors

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, physostigmine salicylate, JWS-USC-75IX, P1 1467, 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- glucopyranoside (NSC-404560), scopolin (SCN), scopoloside, BW-284c51 , withaferin A (NSC-101088), withaferine (NSC-273757), (+)-corynoline, corynoline, (S)-(-)-oxypeucedanin, oxypeucedanin, (-)-voacangine, carbomethoxyibogaine, voacangine, dieckol, phlorofucofuroeckol (PFF), phlorofucofuroeckol A, (-)-3-0-acetylspectaline hydrochloride and rhaphiasaponin 1 , or salts, free bases, racemates or enantiomers thereof.

Diseases related to a deregulation in the expression or activity of cholinesterase

As indicated above, 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. Wesnes KA et a/.], dementia with argyrophilic grains (AG) [Fortschr Neurol Psychiatr, 2005, 73(9), 495-503. Dementia with argyrophilic grains. Lang CJ et a/.], Parkinson's disease or condition [Expert Opin Drug Metab Toxicol, 2009, 5(8), 941-55. Rivastigmine in Parkinson's disease dementia. Chitnis S. & Rao J.], essential tremor and tardive dyskinesia [Consult Pharm., 2006, 21(1), 58-71. Nonparkinsonism movement disorders in the elderly. Chen J.J. & Lee KC], progressive supranuclear palsy [Alzheimers Dement, 2010, 6(1), 70-4. Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis. Liepelt I. et a/.], prion disease [Mol Cell Neurosci, 2009, 40(2), 217-24. Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process. Pera M. et a/.], attention deficit hyperactivity disorder (ADHD) [J Med Assoc Thai. 2005, 88(4), 357-62. Advances in alternative pharmacotherapy of ADHD. Pityaratstian N.], mild cognitive impairment [Gender Med 2009, 6, 345-55. Treatment response to rivastigmine in mild cognitive impairment: an enhanced statistical modeling approach. Ferris S et al; Eur J Nucl Med Mol Imaging, 2008, 35(1): 25-9. Acetylcholine esterase activity in mild cognitive impairment and Alzheimer's disease. Herholz K.], Down syndrome [Lancet, 1999, 353, 1064-5. Cholinergic therapy for Downs' syndrome. Kishnani PS et al.], trau matic brain i nju ry [J Neuropsychiatry Clin Neurosci, 2009, 21(4), 362-70. Psychopharmacological treatment for cognitive impairment in survivors of traumatic brain injury: a critical review. Writer BW & Schillerstrom JE.], migraine [Headache, 2002, 42(7), 596-602. Central cholinergic challenging of migraine by testing second- generation anticholinesterase drugs. Nicolodi M et al.], systemic amyloidosis or condition [Neurochemistry International, 2001, 38(3), 219-226. Reversible and irreversible acetylcholinesterase inhibitors cause changes in neuronal amyloid precursor protein processing and protein kinase C level in vitro. Pakaski M, Rakonczay Z & Ka s a P .] , H u nti ngton 's d isease [Neurotherapeutics, 2008, 5(2), 181-97. Symptomatic treatment of Huntington disease. Adam OR & Jankovic J.], ataxia [Mov Disord, 2008, 23(8), 1154-60. PET study of brain acetylcholinesterase in cerebellar degenerative disorders. Hirano S et a/.], cognitive impairment in multiple sclerosis [J Neurol Sci., 2006, 245(1-2), 177-81. Anticholinesterasics in the treatment of cognitive impairment in multiple sclerosis. Porcel J & Montalban X.], pain [Anaesthesist, 2005, 54(8), 791-9. Cholinesterase inhibitors. Importance in anaesthesia, intensive care medicine, emergency medicine and pain therapy. Kleinschmidt S, Ziegeler S. & Bauer C], narcolepsy [J Clin Sleep Med, 2006, 2, 71-72. Donepezil in the treatment of narcolepsy. Niederhofer H.], hyperkinesis [Psychiatr Pol., 2002, 36(6), 133-41. Acetylcholinesterase inhibitors-beyond Alzheimer's disease. Kfoszewska I.], Wernicke- Korsakoff disease (WKD) [Clin Neuropharmacol, 2002, 25(1), 1 6-20. Therapeutic effects of an acetylcholinesterase inhibitor (donepezil) on memory in Wernicke- Korsakoff's disease. Sahin HA et a/.], delirium [J Clin Psychopharmacol, 2001, 21(1), 1 18. Successful treatment on nonanticholinergic delirium with a cholinesterase inhibitor. Fischer P.], behavioral dysregulation, apathy, irritability, psychosis, depression, mania, tics, and in the diagnosis of depression, panic, and personality disorders [Curr Psychiatry Rep. 2000 Dec;2(6):473-8. Donepezil and related cholinesterase inhibitors as mood and behavioral controlling agents. Burt T], anorexia nervosa [Expert Opin Investig Drugs, 2009, 18(5), 569-71. Donepezil (aricept) as a treatment for anorexia nervosa: a very feasible therapeutic possibility. Halabe Bucay A.], nociceptive pain [J Pharmacol Exp Ther, 1997, 282, 86-92. Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition. Hood D.D. et al.], neuropathic pain [Anesthesiology, 2001, 95(4), 1007-12. Antiallodynic effect of intrathecal neostigmine is mediated by spinal nitric oxide in a rat model of diabetic neuropathic pain. Chen S.R. et al.], autism spectrum disorders (ASD) [Ann Clin Psychiatry., 2009, 21(4), 213-36. Novel and emerging treatments for autism spectrum disorders: a systematic review. Rossignol DA.], stimulant addiction [CNS Drugs., 2009, 23(11), 939-52. Cholinergic functioning in stimulant addiction: implications for medications development. Sofuoglu M. & Mooney ], myasthenia gravis (ocular, generalized myasthenia gravis, seronegative or seropositive patients) [Rev Neurol., 2009, 165(2), 149-54. Therapeutic strategy in myasthenia gravis. Tranchant C], , poststroke aphasia [Neurology., 2006, 67(9), 1687-9. A randomized, placebo-controlled study of donepezil in poststroke aphasia. Berthier M.L. et al.], poisoning [Curr Med Chem., 2009, 16(23), 2977-86. Chemical aspects of pharmacological prophylaxis against nerve agent poisoning. Bajgar J. et ai.], schistosomiasis [Parasitology, 2009, 136(13), 1837-49. Treatment of urinary schistosomiasis: methodological issues and research needs identified through a Cochrane systematic review. Danso-Appiah A. et al.] or glaucoma [J Ocul Pharmacol Then, 2006, 22(1), 62-7. Effect of oral donepezil on intraocular pressure in normotensive Alzheimer patients. Estermann S. et al.]

For further details regarding AChE inhibitors and their use as potential treatments for these pathologies, please see Pharmacological Research 2004, 50, 433-440; Current Medical Research & Opinion 2009, 25(10), 2439-2446; Current Alzheimer Research 2009, 6(2), 86-96.

Glycogen synthase kinase-3 (GSK-3)

Glycogen synthase kinase-3 (GSK-3 or GSK3) is a serine/threonine protein kinase comprised of a and β 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.

Diseases related to a Glycogen synthase kinase-3 (GSK3) deregulation

Deregulation (usually increase) of 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.].

Regarding neurodegenerative disorders and other CNS pathologies, GSK-3 deregulation has been related to Alzheimer's disease [Brain Res Bull., 2009, 80(4-5), 248-50. The role of GSK3 in Alzheimer disease. Hernandez F. et al.], Parkinson's disease [Neuroscience Letters 2009, 449(2), 103-107. 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. et al.], 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) and other tauopathies [Curr Alzheimer Res., 2005, 2(1), 3-18; Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies; Ferrer I. et al.], AIDS associated dementia [J Neuroimmune Pharmacol., 2007, 2(1), 93-96. 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. Roew M.K. et al.; Bipolar Disord., 2002, 4(2), 137-144. 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. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Beaulieu J.M. et al.], Down's syndrome [FASEB J., 2008, 22(9), 3224-33. Overexpression of DyrkIA contributes to neurofibrillary degeneration in Down syndrome. Liu F. et al.], diseases associated with ischemia/reperfusion and shock [Shock., 2007, 27(2), 113-23. Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation. Dugo L. et a/.], brain injury [Neurol Res., 2001, 23(6), 588-92. 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. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). 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. et a/.], spinocerebellar ataxia type 1 [PLoS Med, 2007, 4(5), 836-847. Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. Watase K. et al.], cerebral bleeding for example, due to solitary cerebral amyloid angiopathy [Neuroscience., 2008, 153(2), 414-27. Accumulation of beta-amyloid in the brain microvessels accompanies increased hyperphosphorylated tau proteins following microsphere embolism in aged rats. Han F. et a/.] 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/.].

In addition to its possible relevance to prevent neurodegeneration, 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/.].

During the last few years, 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. The role of protein phosphorylation in human health and disease. Cohen P.], 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. et a/.], peritonitis [Immunity, 2006, 24, 563-574. 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. Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3(beta) phosphorylation in a mouse model of asthma. Bentley J.K. et a/.], sepsis [J. Biochem. Cell. Biol., 2005, 37, 2226-2238. 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. et a/.], inflammation-induced organ injury caused by hemorrhage and resuscitation [Shock, 2006, 25, 485-491. Glycogen synthase kinase-3b inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation. Dugo, L. et a/.], inflammatory injury in chronic renal allograft disease [Am J Transplant., 2008, 8(9), 1852-63. Glycogen synthase kinase 3beta: a novel marker and modulator of inflammatory injury in chronic renal allograft disease. Gong R. et a/.] or lupus [Int. J. Immunopharmacol., 1995, 17, 581-592. Lithium chloride enhances survival of NZBAA/ lupus mice: influence of melatonin and timing of treatment. Lenz, S.P. et a/.].

Among cardiovascular disorders related to GSK-3 are heart disease [Circ. Res., 2002, 90, 1055-63. 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. Clin. Invest, 2002, 109(3), 373-381. Fas receptor signaling inhibits glycogen synthase kinase 3β 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.].

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. et a/.], fragile X syndrome (FXS) [Biochem Pharmacol., 2010, 79(4), 632-46. Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome. Yuskaitis C.J. et a/.] or glaucoma [J Clin Invest, 2008, 118(3), 1056-64. Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure. Wang W.H. et al.]. GSK-3 inhibitors

For a further review of GSK-3 inhibitors and their use as potential treatments for these pathologies, please reference to Nature Reviews, 2004, 3, 479-487. GSK3 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.

Several GSK-3 inhibitors like indirubines [J. Biol. Chem., 2001, 276, 251-60. Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?. Leclerc, S. et al.], maleimides [Bioorg. Med. Chem. Lett, 2001, 11, 635-9. 3-Anilino- 4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Smith, D. et al.], 3-amino pyrazoles [Bioorg. Med. Chem. Lett, 2003, 13, 1581-4. 5-arylpyrazolo[3,4-b]pyridazines: potent inhibitors of glycogen synthase kinase-3 (GSK-3). Witherington, J. et al.], paullones [Eur. J. Biochem., 2000, 267, 5983-94. Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Leost, M. et al.], thiazoles [J. Biol. Chem., 2003, 278, 45937-45. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. Bhat, R. et al.] o r thiadiazolidinones [J. Med. Chem., 2002, 45, 1292-9. First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. Martinez, A. et al.]. 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.

Some thiadiazolidinediones were firstly disclosed as GSK-3 inhibitors in the

International Patent Application WO 01/85685. Subsequently, additional thiadiazolidinediones have been disclosed for example in J. Med. Chem. 2002, 45, 1292-1299 and WO 05/971 17.

The above documents are herewith incorporated by reference, specifically in what regards the preparation of thiadiazolidinedione derivatives.

SUMMARY OF THE INVENTION

It has been found that the combined treatment with a cholinesterase inhibitor and a thiadiazolidinedione derivative shows important advantages with respect to the treatment with cholinesterase inhibitors alone, i n creas i n g the efficacy of th e cholinesterase inhibitor treatment, and reducing the adverse effects in most System- Organ Classes.

Therefore, according to a first aspect, 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:

wherein:

R^a and R^b are independently selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, cycloalkyl, aryl, -(Z)_n-aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzo-fused heterocyclic ring system having 2 or 3 rings, -OR', -C(0)R\ -C(0)OR',-(Z)_n-C(0)OR' and -S(0)_t- Z is independently selected from -C(R')(R")-, -C(O)-, -0-, -C(=NR , -S(0)_t - and

N(R ;

n is zero, one or two;

t is zero, one, two or three;

R' and R" are independently selected from hydrogen, alkyl, aryl and heterocyclic or may together form a C=0 group;

According to a further aspect, the present invention is related to 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. Another aspect of the present invention is a medical kit comprising

(i) a supply of thiadiazolidinedione derivative of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, in dosage units, wherein each of said dosage units contains a therapeutically effective amount of said thiadiazolidinedione derivative or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant and/or vehicle, and

(ii) instructions for administering said thiadiazolidinedione derivative in combination with a cholinesterase inhibitor, or a pharmaceutically acceptable salt or solvate thereof.

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.

According to another aspect, 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.

BRIEF DESCRIPTION OF THE FIGURES

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.

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.

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.

DEFINITIONS

In the present application the following terms have the meaning as indicated: "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.

The term "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.

The term "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. In an embodiment of the invention, the heteroayl group has 3 to 15 members. In a particular embodiment it has 4 to 8 members. Illustrative examples of 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. Preferably, 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

3-to 15 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5- or 6-membered ring with one or more heteroatoms. For the purposes of this invention, 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. Examples of such 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 linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl or naphthyl and aralkyl such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

DETAILED DESCRIPTION OF THE INVENTION

We have made clinical studies comparing the treatment with cholinesterase inhibitors a l o n e wi th th e co m b i n ati o n of ch o l i n este ra s e i n h i b ito rs a n d a thiadiazolidinedione derivative.

Unexpectedly and surprisingly, it has been found that the combined treatment with a thiadiazolidinedione derivative and a cholinesterase inhibitor causes a reduction of the incidence of adverse effects, when classified by System-Organ Classes (further details are given in the EXAMPLES), than the treatment only with a cholinesterase inhibitor. Especially unexpected is the reduction in gastrointestinal adverse effects, which are typical and frequent side effects of the treatment with cholinesterase inhibitors. The results show that the adverse effects occurring during the treatment with cholinesterase inhibitors are reduced by co-administering the thiadiazolidinedione derivative, without significantly adding adverse effects, when classified by System- Organ Classes. These statements will be further detailed and supported in the EXAMPLES.

Further, 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.

As detailed above, the present invention refers to the following aspects:

a combination of at least one thiadiazolidinedione derivative of formula (I) and at least one cholinesterase inhibitor;

a pharmaceutical 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 combination or a composition or a kit for use as a medicament;

a thiadiazolidinedione derivative as defined above, for use in the reduction of side effects caused by the treatment with a cholinesterase inhibition;

- 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 co-administration of at least one cholinesterase inhibitor;

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.

In all of the above aspects, according to a preferred embodiment, 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;

R^c , R^d are independently selected from hydrogen and alkyl, or R^c and R^d together can form a group =0;

Ri , R2, R3, R₄, R5 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, - COR₇, -C(0)OR₇, -C(0)N R₇R₈ -C=NR₇, -CN, -OR₇, -OC(0)R₇, -S(0)_t-R₇, -NR₇R₈, - NR₇C(0)R₈, -NO2, -N=CR₇R₈ or halogen,

t is zero, one, two or three,

R₇ a n d R₈ 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;

or a pharmaceutically acceptable salt or solvate thereof.

Preferably, in the above aspects the thiadiazolidinedione derivative

from the following compounds:

4-benzyl-2-phenethyl-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-diphenylmethyl-1 ,2,4-thiadiazolidine-3,5-dione,

4-benzyl-2-naphthalen-1 -yl-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(4-methoxy-benzyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(4-phenoxy-phenyl)-[1 ,2,4]thiadiazolidine-3,5-dione, 4-benzyl-2-(2-tert-butyl-6-methyl-phenyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(4-methyl-benzyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(2-benzyl-phenyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

2-benzo[1 ,3]dioxol-5-yl-4-benzyl-[1 ,2,4]thiadiazolidine-3,5-dione, and

4-benzyl-2-methyl-1 ,2,4-thiadiazolidine-3,5-dione,

or a pharmaceutically acceptable salt or solvate thereof.

More preferably, the thiadiazolidinedione derivative is 4-benzyl-2-naphtalen-1 -yl-

1 ,2,4-thiadiazolidine-3,5-dione.

Further preferred embodiments are the compounds and general formulas disclosed in WO 01/85685 and WO 05/971 17, which are herewith incorporated by reference.

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.

Preferably, 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.

According to a further preferred embodiment, 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, velnacrine maleate (HP-029, P83-6029A), epastigmine tartrate (L-693487), ipidacrine, zanapezil, ganstigmine, icopezil maleate (CP-1 18954, CP-1 18954-1 1 ), KW 5092, quilostigmine (HP-290, NXX-066), SM 10888, T 82, TAK 802, zifrosilone MDL-73745), BGC 201259, CHF 2060, CI 1002, E 2030, ER 127528, ET 142, F 3796, huprine X, MF 247, MF 268 bitartrate, MF 8615, P 26, PD 142012, RO 465934, SS 20, thiatolserine, tolserine tartrate, UR 1827, 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- 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- glucopyranoside (NSC-404560), scopolin (SCN), scopoloside, BW-284c51, withaferin A (NSC-101088), withaferine (NSC- 273757), (+)-corynoline, corynoline, (S)-(-)-oxypeucedanin, oxypeucedanin, (-)- voacangine, carbomethoxyibogaine, voacangine, dieckol, phlorofucofuroeckol (PFF), phlorofucofuroeckol A, (-)-3-0-acetylspectaline hydrochloride and rhaphiasaponin 1, or pharmaceutically acceptable salts, free bases, racemates or enantiomers thereof.

More preferably, the cholinesterase inhibitor is selected from the group consisting of Donepezil, Galantamine and Rivastigmine.

According to a preferred embodiment, the cholinesterase inhibitor and the thiadiazolidinedione derivative form part of the same medicament.

According to a further preferred embodiment, 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. Alternatively, the separate medicament comprising the cholinesterase inhibitor may be administered at a different time than the medicament comprising the thiadiazolidinedione derivative.

In the above aspects, 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, amyotrophic lateral sclerosis, chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis, arthritis, peritonitis, systemic inflammation, renal dysfunction and hepatotoxicity in endotoxemia, asthma, sepsis, colitis, inflammation-induced organ injury caused by hemorrhage and resuscitation, inflammatory injury in chronic renal allograft disease, lupus, heart disease, atherosclerosis, hypertension, restenosis, leukopenia, metabolic syndrome X, hair loss, severe acute respiratory syndrome coronavirus cocaine addiction, bone loss and glaucoma.

In the above aspects, 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, Wernicke-Korsakoff disease (WKD), delirium, behavioural dysregulation, apathy, irritability, psychosis, depression, mania, tics, panic, personality disorders, anorexia nervosa, autism spectrum disorders (ASD), stimulant addiction, poststroke aphasia, poisoning, schistosomiasis and glaucoma.

Therefore, according to a further embodiment, 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 diseases afflicting the CNS, ataxia, spinocerebellar ataxia type 1 , cerebral bleeding due to solitary cerebral amyloid angiopathy, amyotrophic lateral sclerosis, chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis, arthritis, peritonitis, systemic inflammation, renal dysfunction and hepatotoxicity in endotoxemia, asthma, sepsis, colitis, inflammation-induced organ injury caused by hemorrhage and resuscitation, inflammatory injury in chronic renal allograft disease, lupus, heart disease, atherosclerosis, hypertension, restenosis, leukopenia, metabolic syndrome X, hair loss, severe acute respiratory syndrome coronavirus, stimulant addiction, cocaine addiction, bone loss, glaucoma, mild cognitive impairment, drug-induced dyskinesia, pain, neuropathic pain, nociceptive pain, poisoning, hypersomnia, smoking withdrawal, HIV infections, schistomatosis, urinary incontinence, xerostomia, essential tremor and tardive dyskinesia, prion disease, migraine, systemic amyloidosis or condition, cognitive impairment in multiple sclerosis, narcolepsy, hyperkinesis, Wernicke-Korsakoff disease (WKD), delirium, behavioural dysregulation, apathy, irritability, psychosis, mania, tics, panic, personality disorders, anorexia nervosa, autism spectrum disorders (ASD), myasthenia gravis, poststroke aphasia or schistosomiasis.

According to a particularly preferred embodiment, the disease is selected from

Alzheimer's Disease, Parki nson's d isease, amyotrophic lateral sclerosis and progressive supranuclear palsy.

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.

For example, in the case of Donepezil, 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.

In the case of Galantamine, 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. In the case of Rivastigmine, 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.

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. For example, both drugs may be administered as an oral medicament; or both drugs may be administered as a subcutaneous medicament; etc.

When the effective amounts of the thiadiazolidinedione derivative and the cholinesterase inhibitor are comprised in separate medicaments, 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. For example, both the medicament comprising the thiadiazolidinedione derivative and the medicament comprising the cholinesterase inhibitor may be administered orally. As another example, 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.

In the above defined medical kit, according to a preferred embodiment, 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.

In the following, the invention is further illustrated in the following examples.

They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. EXAMPLES

An exploratory Phase lla study with the thiadiazolidinedione derivative 4-benzyl- 2-naphtalen-1 -yl-1 ,2,4-thiadiazolidine-3,5-dione was performed, in order to evaluate the safety and tolerability of four escalated doses of the thiadiazolidinedione derivative. The study was performed with 30 patients, currently receiving a cholinesterase inhibitor treatment (particularly, Donepezil, Galantamine or Rivastigmine), on a stable and well tolerated dosage for at least 2 months prior to baseline evaluation; the cholinesterase inhibitor treatment was maintained constant during the duration of the study. 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. Patients in Active and Placebo groups were well balanced for demographics, med ical h istory, d isease stage and d u ration , concom itant m ed ication and anticholinesterasic treatment. Regarding the anticholinesterasic treatment, the following was the detailed distribution of the particular anticholinesterasic treatments among the patients:

The protocol established the following escalating regime for the thiadiazolidinedione derivative: Weeks No. Once daily dose

Weeks 1-4 400 mg

Weeks 5-8 600 mg

Weeks 9-14 800 mg

Weeks 15-20 1 ,000 mg

During the study, adverse events were monitored by the study staff.

Further, efficacy endpoints related to the assessment of cognition and global functioning were monitored at baseline and regularly throughout the study. In addition, Global Clinical Assessment was performed at the end of the double-blind period.

The patients that were administered placebo worsened their state during the study in comparison with the baseline, according to several clinical instruments which will be further detailed hereinafter. It has been found that the state of the patients being administered Active was not only not worsened, but even improved, by the combined treatment with a thiadiazolidinedione derivative and a cholinesterase inhibitor, after a treatment of only 20 weeks. While patients only receiving treatment with cholinesterase inhibitors presented a detectable decline of their mental and physical state during this period of time, patients on the combined treatment not only did not further decline during this period, but even improved their mental and physical state. Further details are given in FIGURES.

The main efficacy determinations were:

1 ) Mini-Mental State Examination (MMSE)

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.

2) Alzheimer's Disease assessment Scale (ADAS-cog+)

Cognition was assessed using the modified ADAS-cog (ADAS-cog+), which is 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. For further detail, see for example Alzheimer Dis Assoc Disord. 2004, 18(4), 236-40, which is herewith incorporated by reference.

3) Global Clinical Assessment

At the end of the study 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.

EFFICACY

Example 1 : Mini-Mental State Examination (MMSE)

The MMSE score for each patient, both for the patients being administered Placebo or Active, was determined at the beginning of the Phase l la study, before administrating neither Placebo nor Active, and at the end of the study, once the 20 weeks of study were completed and the last dose was administered. In Figure 1 , the mean change in MMSE score from baseline (considered "0"), in absolute figures, for both Placebo and Active groups, are shown.

As may be observed, 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.

Meanwhile, the patients being administered Active, not only did not decline, maintaining the same MMSE score, but even experienced an improvement with respect to the baseline value, specifically a mean value of 0.56 points in the MMSE scale.

Therefore, a clear improvement in the MMSE 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. No significant differences in the results were detected with regard of the particular anticholinesterasic treatment of the patients (Donepezil, Galantamine or Rivastigmine).

Example 2: Alzheimer's Disease assessment Scale (ADAS-cog+)

The ADAS-cog+ score for each patient, both for the patients being administered

Placebo and Active, was determined several times along the phase lla study (baseline, week 4, week 8, week 14 and week 20).

In Figure 2, the mean change in ADAS-cog+ score from baseline (considered

"0"), in absolute figures, for both Placebo and Active groups, are shown.

As may be observed, the patients being administered Placebo suffered an increase in the ADAS-cog+ score during the 20 weeks, specifically by a mean value of

3.13 points in the ADAS-cog+ score, according to the expected rate of around 6 to 8 points per year, which means that their neurodegenerative disease continued worsening during the study.

Meanwhile, 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.

Therefore, 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.

No significant differences in the results were detected with regard of the particular anticholinesterasic treatment of the patients (Donepezil, Galantamine or Rivastigmine). Example 3: Global Clinical Assessment

At the beginning and the end of the study the overall clinical state of the patients was evaluated, in order to establish a comparison between their basal state and final state, using a seven point scale. In Figure 3, the global results for all the patients that have participated in the study are shown. As may be observed, the clinical state evolution in the Placebo group is comprised between slightly better and much worse, while in the Active group it is comprised between slightly better and slightly worse, the highest percentages being found at similar and slightly better. Therefore, evolution of the clinical state of the patients is clearly improved in the patients receiving a concurrent treatment with a cholinesterase inhibitors and the Active, in comparison with those patients being treated with a cholinesterase inhibitor alone, despite the relatively short duration of the study, i.e. 20 weeks.

No significant differences in the results were detected with regard of the particular anticholinesterasic treatment of the patients (Donepezil, Galantamine or Rivastigmine).

ADVERSE EVENTS

Example 4: Adverse Events by System-Organ Classes

All the adverse events that occurred during the Phase lla study were monitored, both in the placebo and the Compound population. The observed adverse events were classified in the following System-Organ Classes:

Cardiac disorders

Ear and labyrinth disorders

Eye disorders

Gastrointestinal disorders

General and administration disorders

Infections and infestations

Injuries

Investigations and laboratory results

Metabolism and nutrition disorders

Musculoskeletal disorders

Psychiatric disorders

Nervous System disorders

Renal and urinary disorders

Respiratory and thoracic disorders

Skin disorders

Vascular disorders

Particularly, the following particular adverse events were classified within the above classes: Cardiac disorders:

Bradycardia

- Ear and labyrinth disorders:

Vertigo

- Eye disorders:

Diplopia, eyelid oedema

- Gastrointestinal disorders:

Abdominal pain, constipation, diarrhoea, eructation, pale faeces, flatulence, frequent bowel movements, nausea

- General and administration disorders

Fatigue, inflammation, vessel puncture site haematoma

- Infections and infestations

Erysipelas, herpes virus infection

Injuries

Excoriation, fall, skin laceration

- Investigations and lab. Results

Altered blood levels, blood pressure and weight; breath sounds

- Metabolism and nutrition disorders

Folate deficiency, vitamin B12 deficiency

- Musculoskeletal disorders

Arthralgia, limb discomfort, muscle spasms, temporomandibular joint syndrome

- Psychiatric disorders

Apathy

- Nervous System disorders

Aura, dizziness, headache, somnolence

- Renal and urinary disorders

Micturition urgency

- Respiratory and thoracic disorders

Cough

- Skin disorders

Acne, pruritus

Vascular disorders

Haematoma, hypertension, orthostatic hypotension The statistics of the observed adverse events are shown in Figure 4. Both the absolute number (n) of patients and the percentage within each of the administration groups, i.e. Active and Placebo, is indicated. In the right column, the group with highest percentage is indicated.

As may be observed, unexpectedly and surprisingly, in 12 out of 16 System-

Organ Classes, 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.

Claims

1 ) A combination of at least one thiadiazolidinedione derivative of formula (I):

wherein:

R^a and R^b are independently selected from hydrogen, substituted or unsubstituted C1 - C6 alkyl, cycloalkyl, aryl, -(Z)_n-aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzo-fused heterocyclic ring system having 2 or 3 rings, -OR', -C(0)R\ -C(0)OR',-(Z)_n-C(0)OR' and -S(0)_t- Z is independently selected from -C(R')(R")-, -C(O)-, -0-, -C(=NR')-, -S(0)_t - and N(R ;

n is zero, one or two;

t is zero, one, two or three;

R' and R" are independently selected from hydrogen, alkyl, aryl and heterocyclic or may together form a C=0 group; 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.

2) A combination according to claim 1 , wherein the thiadiazolidinedione derivative has formula (II):

wherein:

t is zero, one, two or three,

or a pharmaceutically acceptable salt or solvate thereof.

3) The combination according claim 1 , wherein the thiadiazolidinedione derivative of formula (I) is selected from:

4-benzyl-2-phenethyl-[1 ,2,4]thiadiazolidine-3,5-dione, 4-benzyl-2-diphenylmethyl-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-naphthalen-1 -yl-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(4-methoxy-benzyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(4-phenoxy-phenyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(2-tert-butyl-6-methyl-phenyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(4-methyl-benzyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-(2-benzyl-phenyl)-[1 ,2,4]thiadiazolidine-3,5-dione,

2-benzo[1 ,3]dioxol-5-yl-4-benzyl-[1 ,2,4]thiadiazolidine-3,5-dione,

4-benzyl-2-methyl-[1 ,2,4]thiadiazolidine-3,5-dione,

or a pharmaceutically acceptable salt or solvate thereof.

4) The combination according to claim 3, wherein the thiadiazolidinedione derivative is 4-benzyl-2-naphtalen-1 -yl-1 ,2,4-thiadiazolidine-3,5-dione.

5) The combination according to any one of claims 1 to 4, wherein the cholinesterase inhibitor is selected from the group consisting 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, velnacrine maleate (HP-029, P83-6029A), epastigmine tartrate (L-693487), ipidacrine, zanapezil, ganstigmine, icopezil maleate (CP-1 18954, CP-1 18954-1 1 ), KW 5092, quilostigmine (HP-290, NXX-066), SM 10888, T 82, TAK 802, zifrosilone MDL-73745), BGC 201259, CHF 2060, CI 1002, E 2030, ER 127528, ET 142, F 3796, huprine X, MF 247, MF 268 bitartrate, MF 8615, P 26, PD 142012, RO 465934, SS 20, thiatolserine, tolserine tartrate, UR 1827, 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, physostigmine salicylate, JWS-USC-75IX, P1 1467, 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- glucopyranoside (NSC-404560), scopolin (SCN), scopoloside, BW-284c51 , withaferin A (NSC-101088), withaferine (NSC- 273757), (+)-corynoline, corynoline, (S)-(-)-oxypeucedanin, oxypeucedanin, (-)- voacangine, carbomethoxyibogaine, voacangine, dieckol, phlorofucofuroeckol (PFF), phlorofucofuroeckol A, (-)-3-0-acetylspectaline hydrochloride and rhaphiasaponin 1 , or pharmaceutically acceptable salts or solvates thereof.

6) The combination according to claim 5, wherein the cholinesterase inhibitor is selected from the group consisting of Donepezil, Galantamine and Rivastigmine, or a pharmaceutically acceptable salt or solvate thereof.

7) A pharmaceutical composition comprising a therapeutically effective amount of at least one thiadiazolidinedione derivative of formula (I) as defined in any one of claims 1 to 4, 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.

8) A medical kit comprising (i) a supply of thiadiazolidinedione derivative as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, in dosage units, wherein each of said dosage units contains a therapeutically effective amount of said thiadiazolidinedione derivative or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant and/or vehicle, and (ii) instructions for administering the thiadiazolidinedione derivative in combination with a cholinesterase inhibitor, or a pharmaceutically acceptable salt or solvate thereof.

9) A medical kit according to claim 8, further comprising (iii) a supply of a cholinesterase inhibitor, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant and/or vehicle.. 10) A combination according to any one of claims 1 to 6 or a composition according to claim 7 or a kit according to any one of claims 8 or 9 for use as a medicament.

1 1 ) A combination according to any one of claims 1 to 6 or a composition according to claim 7 or a kit according to any one of claims 8 or 9 for use in the treatment of a GSK3 or cholinesterase mediated disease. 12) A combination or composition or kit according to claim 1 1 , wherein the disease 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, prog ressive su pra n u cl ea r pa l sy, su bacute pan en ceph a l itic pa rki nson is m , 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 diseases afflicting the CNS, ataxia, spinocerebellar ataxia type 1 , cerebral bleeding due to solitary cerebral amyloid angiopathy, amyotrophic lateral sclerosis, chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis, arth ritis, periton itis, system ic i nflam mation , renal dysfunction and hepatotoxicity in endotoxemia, asthma, sepsis, colitis, inflammation-induced organ injury caused by hemorrhage and resuscitation, inflammatory injury in chronic renal allograft disease, lupus, heart disease, atherosclerosis, hypertension, restenosis, leukopenia, metabolic syndrome X, hair loss, severe acute respiratory syndrome coronavirus, stimulant addiction, cocaine addiction, bone loss, glaucoma, mild cognitive impairment, drug-induced dyskinesia, pain, neuropathic pain, nociceptive pain, poisoning, hypersomnia, smoking withdrawal, HIV infections, schistomatosis, urinary incontinence, xerostomia, essential tremor and tardive dyskinesia, prion disease, migraine, systemic amyloidosis or condition, cognitive impairment in multiple sclerosis, narcolepsy, hyperkinesis, Wernicke-Korsakoff disease (WKD), delirium, behavioural dysregulation, apathy, irritability, psychosis, mania, tics, panic, personality disorders, anorexia nervosa, autism spectrum disorders (ASD), myasthenia gravis, poststroke aphasia or schistosomiasis. 13) A combination or composition or kit according to claim 1 1 for the treatment of

Alzheimer's Disease.

14) A thiadiazolidinedione derivative as defined in any one of claims 1 to 4, for use in the reduction of side effects caused by the treatment with a cholinesterase inhibitor.