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WO 2017/182464 Al 26 October 2017 (26.10.2017) W !P O PCT

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WO 2017/182464 Al 26 October 2017 (26.10.2017) W !P O PCT (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 WO 2017/182464 Al 26 October 2017 (26.10.2017) W !P O PCT (51) International Patent Classification: (74) Agent: CARBONELL VALLES, Enric; ABG PATEN C07D 401/14 (2006.01) C07D 209/70 (2006.01) TES, S.L., Avda. de Burgos, 16D , Edificio EUROMOR, A61K 31/403 (2006.01) C07D 209/72 (2006.01) E-28036 Madrid (ES). A61K 31/4439 (2006.01) A61P 3/00 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 31/454 {2006.01) A61P 9/00 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 401/06 (2006.01) A61P 25/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, C07D 409/06 (2006.01) A61P 29/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C07D 409/14 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, PCT/EP20 17/059 178 KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 18 April 2017 (18.04.2017) SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Langi English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 16382175.4 19 April 2016 (19.04.2016) EP UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicants: CIDQO 2012, S.L. [ES/ES]; Poligono Indus TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, trial Can Verdalet, Carred D, Nau 91, E-08490 Tordera EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, - Barcelona (ES). UNIVERSITAT DE BARCELONA MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, [ES/ES]; Centra de Patentes UB, Baldiri Reixac, 4, Torre TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, D, E-08028 Barcelona (ES). KM, ML, MR, NE, SN, TD, TG). (72) Inventors: VAZQUEZ CRUZ, Santiago; Avenida Can Published: Corts, 15, 3-2, E-08940 Cornelia - Barcelona (ES). LEI- — with international search report (Art. 21(3)) VA MARTINEZ, Rosana; Avenida Madrid, 51-53, 1° 5 A, E-08028 Barcelona (ES). VALVERDE MURILLO, Ele¬ na; Abat Escarre, 12, E-4371 1 Banyeres del Penedes - Tar ragona (ES). (54) Title: NEW AZA- TETRACYCLO DERIVATIVES R < (57) Abstract: The present invention relates to compounds of formula (I); which are capable of inhibiting the 11-beta-hydroxysteroid " dehydrogenase type 1 ( 11- beta-HSD 1), to processes for preparing these compounds, to pharmaceutical compositions comprising an effective amount of these compounds, to the use of the compounds in medicine in particular for the treatment of pathological conditions or diseases that can improve by inhibition of 11-beta-HSD 1, to the use of said compound for the manufacture of a medicament for the treatment of pathological conditions or diseases that can improve by inhibition of 11-beta-HSD 1 and to methods for the treatment or - prevention of a disease or conditions susceptible of improvement by inhibition of 11β-hydroxysteroid dehydrogenase type 1( 11β-HD 1) ® in a subject in need thereof comprising the administration to said subject of a therapeutically effective amount of said compounds. NEW AZA- TETRACYCLO DERIVATIVES FIELD OF THE INVENTION The invention relates to new aza-tetracyclo derivatives capable of inhibiting the 11-beta-hydroxysteroid dehydrogenase type 1 ( 11-beta-HSDl). Other objectives of the present invention are to provide a procedure for preparing these compounds; pharmaceutical compositions comprising an effective amount of these compounds; the use of the compounds for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by inhibition of 11-beta-HSDl, such as obesity, insulin resistance, metabolic syndrome, cognitive disfunction associated to Alzheimer's disease, HIV-associated dementia, Creutzfeld- Jakob disease, Parkinson's disease, Huntington's disease, vascular inflammation, atherosclerosis, diabetes type 2, cardiovascular disease, glaucoma, osteoporosis, myocardial infarction and for alcohol abuse treatment. BACKGROUND OF THE INVENTION Glucocorticoids (GCs) are well-known ubiquitous hormones playing a key role in modulating immune and inflammatory responses, regulating energy metabolism and cardiovascular homeostasis and are a key element of stress response. GCs act through the intracellular glucocorticoid receptors and, in some tissues, through mineralocorticoid receptors, both being nuclear transcription factors. The action of GCs on the target tissues depends not only on circulating steroid concentrations and the cellular expression of the receptors, but also on the intracellular enzymes which critically determine up to what point the glucocorticoids will have active access to the receptors. Opposing the action of insulin, GCs promote gluconeogenesis, inhibit β-cell insulin secretion and peripheral glucose uptake. Moreover, GCs contribute to lipolysis, with subsequent fatty acid mobilization, and proteolysis. Thus, overall, GCs prompt catabolic states (e.g., see Dallman, M . F. et al. "Feast and famine: critical role of glucocorticoids with insulin in daily energy flow" in Front. Neuroendocrinal. 1993, 14, 303-347, and Sapolsky, R . M . et al. "How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions" in Endocr. Rev. 2000, 21, 55-89). The active human GC Cortisol, is synthesized by the adrenal cortex with a strong circadian rhythm. Its secretion is controlled by the hypothalamic-pituitary-adrenal (HPA) axis and induced in stressful conditions. Serum Cortisol readily passes cell membranes and exerts its intracellular functions by binding to GC receptors (GRs), which are ligand-activated nuclear receptors. GRs regulate, directly or indirectly, the expression of a plethora of genes involved in various physiological processes (e.g., see Rosen, E . D . "Adipocyte differentiation from the inside out" in Nat. Rev. Mol. Cell. Bio. 2006, 7, 697-706). Furthermore, GCs bind to mineralocorticoid receptors, which regulate blood pressure and sodium balance in the kidney (see Arriza, J. L. et al. "Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor" in Science 1987, 237, 268-275). Along with the F PA axis, GCs homeostasis is controlled by the 11β- hydroxysteroid dehydrogenase enzyme. Two isoforms of this enzyme, Ι ΐ β-HSD type 1 (Ι Ιβ-HSDl) and type 2 (l ip-HSD2), catalyse the interconversion between active 11- hydroxy forms (Cortisol in humans, and corticosterone in rodents) and inert 11- ketosteroids (cortisone in humans, and 11-dehydrocorticosterone in rodents). The 11β- HSD1 enzyme, mainly expressed in liver, adipose tissue, bone, pancreas, vasculature and brain, reconverts inactive glucocorticoids into active ones, thus playing an important role in modulating cellular agonist concentration and, therefore, in activating corticosteroid receptors in the target tissues. METABOLIC DISEASE SYNDROME AND DIABETES Type 2 diabetes mellitus (T2DM) is characterized by increased cellular insulin resistance with an initial phase of enhanced insulin secretion followed by pancreatic β- cell failure. Regarding obesity, a person with a body mass index of 30 or more is considered obese, entailing health risks. T2DM and obesity are considered as first-world epidemics and are nowadays great healthcare challenges in the developed countries. According to the World Health Organization (WHO), in 2014, 9% of the worldwide adult population had diabetes (see WHO web page. Diabetes Fact Sheet, htt ://www.who int/mediacentre/ factsheets/ fs3 2/en/ accessed on 2 1st March 2016). That same year, the percentage of total health expenditure in T2DM reached US $ 612 billion. The expected increase on the diabetic population by 2035 is about 205 million, which will elevate the total health cost still higher (see, European Comission web page. Major and chronic diseases: Diabetes. http://ec.europa.eu/health/major_chronic_diseases/diseases/diabetes/index__en.htm#frag ment7 accessed on 2 1st March 2016). Concerning obesity, in 2014 more than 1.9 billion adults were overweight, and of these, 600 million were obese (WHO web page. Obesity and overweight Fact Sheet http://www.who.int/mediacentre/factsheets/fs3 1l/en/ accessed on 2 1st March 2016). From another standpoint, the metabolic syndrome is a cluster of metabolic abnormalities including resistance to insulin, obesity, hyperglycemia, and hypertension that represents a major risk factor for type-2 diabetes and cardiovascular disease. It is diagnosed in a given patient if visceral obesity and two or more risk factors are present, including elevated fasting plasma glucose, elevated triglycerides, elevated blood pressure and reduced high-density lipoprotein (see Huang, P. L . "A comprehensive definition for metabolic syndrome" in Dis. Model Mech. 2009, 2, 231-237"). Among the mechanisms involved in its pathogenesis, glucocorticoid synthesis and metabolism have been proposed to play a key role (e.g., see Wamil, M . et al. "Inhibition of 11β- hydroxysteroid dehydrogenase type 1 as a promising therapeutic target" in Drug Discover. Today 2007, 12, 504-520). Currently, the predominant therapeutic strategy for preventing or managing T2DM and metabolic syndrome is the individual treatment of the set of risk factors instead of treating the disorder as a whole. The increase in the prevalence of T2DM and metabolic syndrome over the last few decades in the developed countries has propelled a growing need for the development of novel therapies to treat metabolic syndrome and its associated disorders.
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