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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date Χ t it t t 8 December 2011 (08.12.2011) WO 2U11/151359 A l (51) International Patent Classification: (74) Agent: LORCA MELTON, Miguel; ABG Patentes, A61K 31/549 (2006.01) A61K 31/445 (2006.01) S.L., Avda. de Burgos, 16D, Edificio EUROMOR, A61K 45/06 (2006.01) A61K 31/553 (2006.01) E-28036 Madrid (ES). A61K 31/433 (2006.01) A61P 25/28 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 31/27 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, PCT/EP20 11/059007 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 1 June 201 1 (01 .06.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (25) Filing Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (30) Priority Data: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 10382160.9 2 June 2010 (02.06.2010) EP (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): NOSCI- kind of regional protection available): ARIPO (BW, GH, RA, S.A. [ES/ES]; Avenida de la Industria, 52, E-28760 GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Tres Cantos - Madrid (ES). ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (75) Inventors/Applicants (for US only): FERNANDEZ LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SOUSA-FARO, Jose Maria [ES/ES]; Noscira S.a., Avda SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, de la Industria, 52, 28760 Tres Cantos (Madrid) (ES). GW, ML, MR, NE, SN, TD, TG). DEL SER QUIJANO, Teodoro [ES/ES]; Noscira S.a., Avda de la Industria, 52, 28760 Tres Cantos (Madrid) Published: (ES). CESTER SCHLAAK, Helga [ES/ES]; Noscira — with international search report (Art. 21(3)) S.a, Avda de la Industria, 52, 28760 Tres Cantos (Madrid) (ES). (54) Title: COMBINED TREATMENT WITH A CHOLINESTERASE INHIBITOR AND A THIADIAZOLIDINEDIONE DERIVATIVE (57) Abstract: A combination of a chohnesterase inhibitor and a thiadiazolidinedione derivative; a pharmaceutical composition comprising a chohnesterase inhibitor and a thiadiazolidinedione derivative; a medical kit useful for administering in combination a chohnesterase inhibitor and a thiadiazolidinedione derivative; a method or treatment with a combination of a chohnesterase in hibitor and a thiadiazolidinedione derivative. 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 A D 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 A D 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. 60th 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 151 3528, EP 1386607, EP 1323712, EP 0947193 or EP 1047674.
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