Adamantyl oxadiazole derivatives suitable for use as effective and selective inhibitors of the reducing activity of enzyme 11-beta dehydrogenase type 1 (11β-HSD1), as well as pharmaceutically acceptable solvates, hydrates, and salts thereof, pharmaceutical compositions containing them, and synthesis methods.

Abstract

The present invention relates to compounds derived from adamantyl oxadiazoles, and their pharmaceutically acceptable solvates, hydrates, and salts. These compounds are suitable for use as potent and selective inhibitors of the reductase activity of the enzyme 11-beta dehydrogenase type 1 (11β-HSD1) and for the manufacture of medicaments for treating conditions and diseases such as hypertension, obesity, dyslipidemia, type 2 diabetes, insulin resistance, glaucoma, metabolic syndrome, cognitive impairment, osteoporosis, immune disorders, depression, and other conditions. Pharmaceutical compositions containing the compounds and methods for preparing the compositions are also provided.

Description

Detailed description of the invention

[0001] [Technical field] The present invention refers to compounds derived from adamantyloxadiazole and its solvates, hydrates, and pharmaceutically acceptable salts, which are effective as effective and selective inhibitors of the reductase activity of the enzyme 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In particular, the use of compounds derived from adamantyloxadiazole and their pharmaceutically acceptable salts is disclosed as effective in treating diseases and conditions associated with increased cortisol mediated by the reductase activity of the enzyme 11β-HSD1. These diseases include, but are not limited to, hypertension, obesity, dyslipidemia, type 2 diabetes, insulin resistance, glaucoma, metabolic syndrome, cognitive impairment, osteoporosis, depression, and immune disorders, among other conditions. Processes for producing compounds derived from adamantyloxadiazole are also available. [Background technology] Glucocorticoids (GCs) are steroid hormones involved in regulating various physiological and metabolic processes, such as responses to physical and emotional stress. These hormones, naturally produced in the adrenal cortex, can be artificially synthesized and used as anti-inflammatory, anti-allergic, and immunosuppressant drugs derived from cholesterol or hydrocortisone.

[0002] The most important glucocorticoid molecule is cortisol. Cortisol is produced and released in association with the activation of the hypothalamic-pituitary-adrenal axis. This axis is activated after stressful periods, such as when exposed to physical attacks. When activated, the hypothalamus secretes corticotropin-releasing factor (CRF). CRF acts on the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH mediates the activation of the adrenal glands for the release of corticosteroids, among which for the release of cortisol. Once in the bloodstream, cortisol remains bound to plasma proteins such as cortisol-binding globulin (CBG) and albumin, and the same circulates in its free form (10 - 15%) (Kadmiel M. and Cidlowski JA., 2013).

[0003] Once in the target tissues, the activity and concentration of glucocorticoids depend on the 11-β dehydrogenase system. This enzyme system includes the enzymes 11-β hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2). Isoform 1 is mainly expressed in the liver, vascular smooth muscle, adipose tissue, brain, and pancreas, and isoform 2 is mainly found in the colon and kidney.

[0004] Enzyme 11β-HSD1 catalyzes the conversion of cortisone (a physiologically inactive molecule) to cortisol via an oxidation-reduction reaction dependent on the coenzyme NADPH. The reaction mediated by enzyme 11β-HSD1 is a bidirectional reaction and acts as a hydroxysteroid reductase when catalyzing the conversion of cortisone to cortisol, increasing the intracellular level of glucocorticoids. This enzyme binds to the glucocorticoid receptor and quickly binds the produced cortisol to the glucocorticoid receptor to exert its action.

[0005] According to previous studies, in a mouse model with overexpression of the gene encoding the enzyme 11β-HSD1 in the liver, a hypertensive (elevated blood pressure) phenotype was observed, and an increase in the concentration of the hormone aldosterone was also observed (Masuzaki H. et al. 2003). On the other hand, a study using rats with an obese phenotype (Zucker rats) concluded that in the obese state, a deteriorated activity of the hydroxysteroid reductase activity of this enzyme was observed (Livingstone DEW. et al., 2000).

[0006] The action of the reducing enzyme hydroxysteroid was dominant in liver tissue, muscle, and adipose tissue, promoting the conversion of cortisone to cortisol, and a significant increase in the concentration of glucocorticoids in these tissues was observed in vivo (Tomlinson J.W. et al., 2004).

[0007] An increase in the intracellular concentration of cortisol can cause an increase in glucose production in the liver, promote the differentiation of adipocytes, and potentially cause insulin resistance. In this sense, an increase in cortisol concentration at the intracellular level in metabolically important tissues has been associated with the development of diseases such as obesity, diabetes, arterial hypertension, and metabolic syndrome, in particular (Wake D.J. and Walker B.R., 2004; Walker B.R., 2006). <11β-HSD1 enzyme inhibitor> Various 11β-HSD1 enzyme inhibitor compounds have already been described. Documents EP 1474139, WO / 2006 / 000371, WO / 2006 / 024628, US20090227631, EP1814846, US8188288, EP1801098, WO / 2007 / 068330, EP2044004, WO / 2007 / 145835, WO / 2007 / 145835, WO / 2008 / 052638, EP1935420, US7329683, WO 2010139827 A1, EP1918285, US20100069365, US20100022597, and US20100222316 A1 are just examples of documents that refer to inhibitor compounds of this enzyme.

[0008] Document WO / 2006 / 100502 contains formula (I):R 1 -ZR 2 It has been disclosed that the compound is effective as an inhibitor of the enzyme 11β-HSD1. In one embodiment of the present invention, the compound of formula (I) corresponds to a derivative of adamantyloxadiazole. However, this compound further contains a thiophene group in its structure and is structurally different from the compounds that are part of the scope of the present invention.

[0009] Despite the existence of various inhibitory compounds against the 11β-HSD1 enzyme, the compounds already described focus on their mechanisms of action and selectivity for isoforms 1 and 2 of the 11β-HSD1 enzyme, aiming to completely inhibit the action of isoform 1 without distinguishing between the types of enzymatic reactions (acting as reductase or dehydrogenase). Document WO 2006000371 A2, for example, presents pyrimidine-derived compounds as inhibitors of the enzyme 11β-HSD1 that have selective activity against isoform 2 of the enzyme, but does not mention the selectivity of the inhibitors for the reductase or dehydrogenase (oxidase) action of the 11β-HSD1 enzyme.

[0010] The inhibitor described in this application exhibits inhibitory activity against the reductase activity of enzyme 11β-HSD1, increasing its oxidase activity, while simultaneously not inhibiting the action of enzyme 11β-HSD2.

[0011] On the other hand, the inventors have identified novel inhibitory compounds that are specific and selective to the activity of the 11β-HSD1 enzyme, and that achieve the desired therapeutic effect at lower concentrations than those used with other inhibitors. For example, document WO2006100502 A1 presents information regarding the inhibition of the compound described therein, which is effective at a dose of 10 μM. The compound of formula (I) described in this application exhibits inhibitory activity at doses on the order of nM (100 nM).

[0012] In short, the compound of formula (I) exhibits inhibitory activity of the enzyme 11β-HSD1 in a selective and specific manner due to its reductase activity, using lower concentrations to produce the desired therapeutic effect. [Detailed description of the invention] This invention refers to adamantyloxadiazole compounds of formula (I) and their solvates, hydrates, and pharmaceutically acceptable salts:

[0013] [ka]

[0014] Because L is independently a carbon or nitrogen atom, and R1, R2 and R3 are independently hydrogen atoms, F, Br, Cl, NO2, linear or branched C 1-4 Selected from alkyl groups or OR groups, where R is H or linear or branched C. 1-4 This is because it is an alkyl group.

[0015] Examples of preferred compounds of formula (I):

[0016] [ka]

[0017] JPEG0007838792000003.jpg254169

[0018] JPEG0007838792000004.jpg152169

[0019] The object of the present invention is to provide novel inhibitor compounds for the enzyme 11-β dehydrogenase type 1. In particular, the inventors have identified, synthesized, and characterized adamantyloxadiazole type compounds. Adamantyloxadiazole type compounds have advantages over other inhibitor compounds for the enzyme 11β-HSD1 with respect to their specificity for the reductase activity of the enzyme and their selectivity for isoforms 1 and 2 (11β-HSD2). In this sense, the compounds described in this application exhibit inhibitory activity against the reductase activity of the 11β-HSD1 enzyme, increasing its oxidase activity, while simultaneously not affecting the action of the 11β-HSD2 enzyme.

[0020] The inventors have identified novel specific and selective inhibitory compounds of the reductase activity of enzyme 11β-HSD1 in a manner that achieves the desired therapeutic effect by means of concentrations on the order of μM.

[0021] Compounds of formula (I) within the scope of the present invention include both their non-solvated and solvated forms, and their hydrates, including, for example, hemihydrates.

[0022] Another objective of the present invention is to have a pharmaceutically acceptable composition containing an adamantyloxadiazole compound of formula (I).

[0023] The scope of the present invention includes the use of compounds of formula (I), their pharmaceutically acceptable salts, solvates and hydrates, and pharmaceutically acceptable compositions comprising them, for their effectiveness as selective inhibitors of the 11β-HSD1 enzyme. Furthermore, the use of compounds of formula (I), their pharmaceutically acceptable salts, solvates and hydrates, and pharmaceutically acceptable compositions comprising them is disclosed as effective in the preparation of agents for the treatment of conditions and diseases associated with 11β-HSD1 enzyme activity. Conditions and diseases associated with 11β-HSD1 enzyme activity include, among others, hypertension, obesity, dyslipidemia, type 2 diabetes, insulin resistance, glaucoma, metabolic syndrome, cognitive impairment, osteoporosis, depression, and immune disorders.

[0024] The present invention further includes a process for preparing compounds derived from adamantyloxadiazole.

[0025] [Drawing description] [Figure 1] BD40 (nM) levels detected in plasma and other tissues at IV dose (2 mg / kg) over different periods. BD-40 concentrations detected by single-point analysis by LC-MS / MS in different tissues:

[0026] [ka]

[0027] This corresponds to analysis in plasma,

[0028] [ka]

[0029] This corresponds to analysis in brain tissue,

[0030] [ka]

[0031] This corresponds to analysis in the liver,

[0032] [ka]

[0033] This corresponds to the analysis in epididymal fat,

[0034] [ka]

[0035] This corresponds to analysis in muscles.

[0036] [Figure 2] BD40 (nM) levels detected in plasma and other tissues at oral doses (10 mg / kg) over different periods. BD-40 concentrations detected by single-point analysis by LC-MS / MS in different tissues:

[0037] [ka]

[0038] This corresponds to analysis in plasma,

[0039] [ka]

[0040] This corresponds to analysis in brain tissue,

[0041] [ka]

[0042] This corresponds to analysis in the liver,

[0043] [ka]

[0044] This corresponds to the analysis in epididymal fat,

[0045] [ka]

[0046] This corresponds to analysis in muscles.

[0047] [Figure 3] A graph summarizing the levels of BD-44 compound detected in plasma at different time points, IV dose (2 mg / kg), and oral dose (10 mg / kg).

[0048] [ka]

[0049] It supports IV dose detection,

[0050] [ka]

[0051] This corresponds to oral dose detection.

[0052] <Definition> In the present invention, when referring to pharmaceutically acceptable salts, non-toxic salts prepared from the addition of bases or acids suitable for administration in mammals, particularly humans, include those derived from the addition of pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

[0053] Examples of pharmaceutically acceptable acids from which salts can be derived include, but are not limited to, acetic acid, benzoic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucus, nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and xinafoic acid. Particularly preferred salts are those derived from fumaric acid, hydrobromic acid, hydrochloric acid, acetic acid, sulfuric acid, methanesulfonic acid, xinafoic acid, and tartaric acid.

[0054] Salts derived from the addition of pharmaceutically acceptable inorganic bases include, but are not limited to, salts of aluminum, ammonium, calcium, sodium, and zinc. Salts of ammonium, calcium, magnesium, potassium, and sodium are preferred.

[0055] Salts derived from the addition of pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and natural amines. Examples include, but are not limited to, arginine, betaine, caffeine, choline N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, resins, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0056] In the present invention, when referring to solvates including hydrates or other types of solvates, these are formed from the contact of the non-solvated form of the compound of formula (I) and its pharmaceutically acceptable salts with a solvent. Typical solvents include, but are not limited to, water, ethanol, methanol, isopropanol, and acetic acid. In particular, when the solvent corresponds to water, the solvate formed is a hydrate.

[0057] When referring to “diseases or conditions associated with the activity of enzyme 11β-HSD1,” all diseases and / or conditions recognized as currently or potentially associated with increased activity of enzyme 11β-HSD1 and therefore with increased tissue cortisol levels are considered. The diseases and conditions described include, but are not limited to, hypertension, obesity, dyslipidemia, type 2 diabetes, insulin resistance, metabolic syndrome, glaucoma, osteoporosis, cognitive impairment, depression, anxiety, immune disorders, and similar conditions associated with increased cortisol levels produced by enzyme 11β-HSD1.

[0058] The term "therapeutic dose" refers to the amount of medication administered to a patient who needs treatment, which is sufficient to provide that treatment.

[0059] In this invention, when "treatment" is used, it refers to the treatment of a disease, pathological condition or medical condition in a human patient, including: (a) To prevent the onset of a disease or condition as a preventive treatment for a patient; (b) To alleviate a disease or condition and cause its regression; (c) suppressing a disease or medical condition, or delaying the degree of development in a patient, (d) Reducing or alleviating symptoms related to the patient's disease or medical condition.

[0060] [Examples] <Example 1: Synthesis and Characterization of Compound (I)> This example presents the chemical synthesis of a parent compound for the synthesis of a compound of formula (I), which is part of the present invention, and the synthesis of examples of novel compounds derived from adamantyloxadiazole of formula (I), which is part of the scope of the present invention.

[0061] <Synthesis and Characterization of Adamantylamidoxime Parent Compound (1)>

[0062] [ka]

[0063] A mixture of hydroxylamine hydrochloride (2.59 g, 37.2 mmol) and sodium carbonate (3.93 g, 37.1 mmol) was prepared in ethanol (10 mL) and glycerol (10 mL) and stirred overnight at room temperature. Next, a solution of cyanoadamantane (2.00 g, 12.4 mmol) and aluminum chloride (0.25 g, 1.86 mmol) in ethanol (30 mL) was prepared, stirred at room temperature for 30 minutes, and added dropwise to the hydroxylamine-carbonate mixture. The resulting white suspension was vigorously stirred under reflux conditions for 10 hours. The progress of the reaction was monitored by TLC using iodine vapor as the developer. After 10 hours, residual ethanol was removed by vacuum filtration. The residue was partitioned with water and dichloromethane, and the aqueous phase was further extracted with dichloromethane. The resulting organic phase was washed with brine and dried over anhydrous sodium sulfate to obtain a white product. This white product was purified by recrystallization using an acetone-hexane mixture to produce colorless crystals corresponding to adamantylamidoxime (1). The synthesis yield was 85%. Compound melting point (1): 210–215 °C. IR (KBr) cm -1 : 3505 (NH), 3405 (free OH), 3218 (H-bonded OH), 2908-2850 (CH sp3); 1645 (C=N), 1582 (NH2), 1454 (CH2), 1357 (CN). 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 4.51 (s, 2H, -NH2); 1.98 (bs, 6H, H-1); 1.80 (bs, 3H, H-2); 1.67 (m, 6H, H-3). 13 ¹¹C-NMR (ppm) (101°MHz, CDCl3) δ: 159.6; 39.7; 36.6; 36.5; 28.1. Calculated molecular weight: 194.1419 g / mol; Observed molecular weight: 194.1413 g / mol.

[0064] <Synthesis and Characterization of Compound BD-31: 1-Phenyl-2-(3-adamantyl-1,2,4-oxadiazol-5-yl)ethane> A solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (497 mg, 2.83 mmol) in 1,4-dioxane (10 mL) was prepared and stirred at room temperature. N-Methylmorpholine (849 μL, 7.72 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 minutes. Next, a solution of 3-phenylpropionic acid (425 mg, 2.83 mmol) in 1,4-dioxane (5 mL) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Then, a solution of adamantylamidoxime parent compound (1) (500 mg, 2.57 mmol) in 1,4-dioxane (5 mL) was added, and the resulting mixture was vigorously stirred under reflux conditions for 3 hours. The progress of the reaction was monitored by TLC. After 3 hours, the mixture was cooled to room temperature, and 5% sodium carbonate solution was added. The product was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo.

[0065] The obtained crude product was purified by gravity column chromatography using a mixture of 10% ethyl acetate in n-hexane as the eluent. As a further purification step, the product was purified by thin layer chromatography using n-hexane as the eluent to obtain a colorless gel. Melting point: The product in a gel state. IR (KBr) cm -1 : 3086 - 3028 (=C-H sp 2 Ar), 2917 - 2850 (C-H sp 3 ), 1579 (C=N), 1497 (C=C Ar), 1453 (CH2), 1349 (C-N), 1304 - 1026 (C-O). 1 1H-NMR (ppm) (400 MHz, CDCl3) δ: 7.31 (dd, 2H, H-1’’); 7.23 (dd, 3H, H-2’’, H-3’’); 3.16 (m, 4H, H-1’, H-2’); 2.07 (m, 9H, H-1, H-2); 1.81 (bs, 6H, H-3). 13¹¹C-NMR (ppm) (101°MHz, CDCl3) δ: 178.2; 177.0; 139.6; 128.6; 128.3; 126.6; 40.2; 36.5; 34.3; 32.8; 28.6; 28.0. Calculated molecular weight: 308.1889 g / mol; Observed molecular weight: 308.1883 g / mol.

[0066] <Synthesis and Characterization of Compound BD-32: 1-(4-methoxyphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> The compound was prepared from 2-chloro-4,6-dimethoxy-1,3,5-triazine (248 mg, 1.42 mmol), N-methylmorpholine (424 μL, 3.87 mmol), 3-(4-methoxyphenyl)propionic acid (255 mg, 1.42 mmol), and parent compound (1) (250 mg, 1.29 mmol). The crude product was obtained and purified by gravity column chromatography using a mixture of 10% ethyl acetate in n-hexane as the eluent, yielding a white solid. The reaction yield was 42%. Melting point: 48-53°C. IR (KBr) cm -1 : 3066-3003 (=CH sp 2 Ar), 2908-2850 (CH sp 3 ), 1588 (C=N), 1612 (C=C Ar), 1451 (CH2), 1391 (CH3), 1346 (CN), 1301 (CO). 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 7.24 (d, J = 8.0 Hz, 2H, H-1''); 6.96 (d, J = 8.1 Hz, 2H, H-2''); 3.90 (s, 3H, -OCH3); 3.22 (m, 4H, H-1', H-2'); 2.19 (m, 9H, H-1, H-2); 1.93 (bs, 6H, H-3). 13¹¹C-NMR (ppm) (10¹ MHz, CDCl₃) δ: 178.3; 176.9; 158.3; 131.6; 129.2; 114.0; 55.2; 40.2; 36.5; 34.2; 31.9; 28.8; 28.0. Calculated molecular weight: 338.5 g / mol. Observed molecular weight: 338.3 g / mol.

[0067] <Synthesis and characterization of compound BD-33: 1-(4-chlorophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> A mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (497 mg, 2.83 mmol), N-methylmorpholine (849 μL, 7.72 mmol), 3-(4-chlorophenyl)propionic acid (523 mg, 2.83 mmol), and adamantylamidoxime parent compound (1) (500 mg, 2.57 mmol) was prepared, and the product was purified by gravity column chromatography using a mixture of 10% ethyl acetate in n-hexane as the eluent. Further purification was performed by recrystallization from ethanol to obtain a white solid. The reaction yield was 69%. Melting point: 78-83°C. IR (KBr) cm -1 : 3065-3026 (=CH sp 2 Ar), 2908-2848 (CH sp 3 ), 1582 (C=N), 1495 (C=C Ar), 1453 (CH2), 1349 (CN), 1305-1014 (CO), 1094 (C-Cl Ar). 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 7.24 (d, J = 7.9 Hz, 2H, H-2''); 7.11 (d, J = 7.8 Hz, 2H, H-1''); 3.10 (m, 4H., H-1', H-2'); 2.03 (m, 9H, H-1, H-2); 1.77 (bs, 6H, H-3). 13 C-NMR (ppm) (10¹ MHz, CDCl₃) δ: 177.9; 177.0; 137.9; 132.5; 129.7; 128.8; 40.2; 36.5; 34.2; 32.0; 28.4; 28.0. Calculated molecular weight: 342.1499 g / mol; Observed molecular weight: 342.1496 g / mol.

[0068] <Synthesis and characterization of compound BD-34: 1-(4-fluorophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> This compound was prepared from the reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (248 mg, 1.42 mmol), N-methylmorpholine (424 μL, 3.86 mmol), and 3-(4-fluorophenyl)propionic acid (216 mg). The crude product was obtained by 1.29 mmol and 1 (300 mg, 1.54 mmol). This was purified by gravity column chromatography using a mixture of 20% ethyl acetate in n-hexane as the eluent to obtain a white solid. The reaction yield was 56%. Melting point: 62-64°C. IR (KBr) cm -1 :3064-3005 (=CH sp 2 Ar), 2905-2848 (CH sp 3 ), 1579 (C=N), 1604 (C=C Ar), 1453 (CH2), 1348 (CN), 1303-1026 (CO), 1256-1088 (CF Ar). 1 2.05 (bs, 6H, H-3). 13 C-NMR (ppm) (101 MHz, CDCl3) δ: 178.0; 177.0; 161.7 (d, J = 244.7 Hz, 1C); 135.2 (d, J = 3.3 Hz, 1C); 129.8 (d, J = 7.9 Hz, 2C); 115.4 (d, J = 21.3 Hz, 1C); 40.2; 36.5; 34.2; 31.9; 28.7; 28.0. Calculated molecular weight: 326.4 g / mol; Observed molecular weight: 326.4 g / mol.

[0069] <Synthesis and characterization of compound BD-35: 1-(4-bromophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> For this synthesis, a mixture containing 2-chloro-4,6-dimethoxy-1,3,5-triazine (273 mg, 1.56 mmol), N-methylmorpholine (424 μL, 3.86 mmol), 3-(4-bromophenyl)propionic acid (324 mg, 1.42 mmol), and the parent compound adamantylamidoxime (1) (325 mg, 1.67 mmol) was prepared, and the product was purified by gravity column chromatography using a mixture of n-hexane and 10% ethyl acetate as the eluent. Purification yielded a white solid. The reaction yield was 69%. Melting point: 95-100°C. IR (KBr) cm -1 : 3063-3022 (=CH sp 2 Ar), 2908-2846 (CH sp 3 ), 1580 (C=N), 1491 (C=C Ar), 1451 (CH2), 1348 (CN), 1304-1010 (CO), 1072 (C-Br Ar). 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 7.41 (d, J = 8.1 Hz, 2H, H-2''); 7.22 (d, J = 8.0 Hz, 2H, H-1''); 3.11 (sa, 4H, H-1', H-2'); 2.05 (m, 9H, H-1, H-2); 1.79 (bs, 6H, H-3). 13¹¹C-NMR (ppm) (10¹ MHz, CDCl₃) δ: 177.8; 177.0; 138.5; 131.7; 130.1; 120.5; 40.2; 36.5; 34.2; 32.1; 28.3; 27.9. Calculated molecular weight: 386.0994 g / mol; Observed molecular weight: 386.0989 g / mol. <Synthesis and characterization of compound BD-36: 1-(4-methylphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> A mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (273 mg, 1.56 mmol), N-methylmorpholine (466 μL, 4.23 mmol), 3-(p-tolyl)propionic acid (232 mg, 1.42 mmol), and the parent compound adamantylamidoxime (1) (302 mg, 1.56 mmol) was prepared and purified by gravity column chromatography using a mixture of 10% ethyl acetate in n-hexane as the eluent to obtain the product. For further purification, the product was recrystallized from ethanol to provide a white solid. The product yield of the compound was 58%. Melting point: 64-68°C. IR (KBr) cm -1 : 3064-3017 (=CH sp 2 Ar), 2905-2849 (CH sp 3 ), 1584 (C=N), 1516 (C=C Ar), 1452 (CH2), 1387 (CH3), 1348 (CN), 1305-1087 (CO). 1 H-NMR (ppm) (400°MHz, CDCl3) δ: 7.23 (bs, 4H, H-1'', H-2''); 3.24 (m, 4H, H-1', H-2'); 2.45 (s, 3H, -CH3); 2.19 (m, 9H, H-1, H-2); 1.92 (bs, 6H, H-3). 13 C-NMR (ppm) (10¹ MHz, CDCl₃) δ: 178.3; 177.0; 136.5; 136.1; 129.3; 128.2; 40.2; 36.5; 34.3; 32.4; 28.8; 28.0; 21.0. Calculated molecular weight: 322.2045 g / mol; Observed molecular weight: 322.2040 g / mol.

[0070] <Synthesis and Characterization of Compound BD-37: 1-(4-hydroxyphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> A crude product was prepared from 2-chloro-4,6-dimethoxy-1,3,5-triazine (237 mg, 1.56 mmol), N-methylmorpholine (466 μL, 4.25 mmol), 3-(4-hydroxyphenyl)propionic acid (235 mg, 1.42 mmol), and 1 (302 mg, 1.56 mmol). This crude product was purified by gravity column chromatography using a mixture of 20% ethyl acetate in n-hexane as the eluent to obtain a pale yellow gel. Yield: 70%; Melting point: Product in gel state. IR (KBr) cm-1: 3409 (OH bound to H), 3042 (= CH sp2 Ar), 2903-2848 (CH sp3), 1664-1516 (C = C Ar), 1574 (C = N), 1452 (CH2), 1350 (CN), 1305-1026 (heterocyclic CO), 1227 (phenolic CO). 1 H-NMR (ppm) (400 MHz, CDCl3): 7.01 (d, J = 8.3 Hz, 2H, H-1 '); 6.75 (d, J = 8.4 Hz, 2H, H-2 ''); 3.08 (m, 4H, H-1 ', H-2'); 2.05 (m, 9H, H-1, H-2); 1.78 (bs, 6H, H-3). 131C-NMR (ppm) (101 MHz, CDCl3): 178.6; 176.9; 154.7; 131.2; 129.4; 115.6; 40.1; 36.4; 34.3; 31.9; 28.9; 27.9. Calculated molecular weight: 324.4 g / mol. Observed molecular weight: 324.3 g / mol. <Synthesis and characterization of compound BD-38: 1-(3-methoxyphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> This compound was prepared from the reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (268 mg, 1.53 mmol), N-methylmorpholine (458 μL, 4.16 mmol), 3-(3-methoxyphenyl)propionic acid (250 mg, 1.39 mmol), and (296 mg, 1.53 mmol) to obtain the crude product. This was purified by gravity column chromatography using a mixture of 20% ethyl acetate in n-hexane as the eluent to obtain a colorless gel. The yield of the compound was 48%. Melting point: Product in gel state. 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 7.23 (t, J = 7.7 Hz, 1H, H-2''); 6.80 (m, 3H, H-1'', H-3'', H-4''); 3.81 (s, 3H, -OCH3); 3.14 (m, 4H, H-1', H-2'); 2.08 (m, 9H, H-1, H-2); 1.81 (bs, 6H, H-3). 13 C-NMR (ppm) (101 MHz, CDCl3) δ: 178.2; 177.0; 159.8; 141.2; 129.6; 120.6; 114.0; 112.1; 55.2; 40.2; 36.5; 34.3; 32.8; 28.5; 28.0.

[0071] <Synthesis and characterization of compound BD-39: 1-(4-pyridyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> A reaction mixture containing 2-chloro-4,6-dimethoxy-1,3,5-triazine (319 mg, 1.82 mmol), N-methylmorpholine (546 μL, 4.96 mmol), 3-(4-pyridyl)propionic acid (250 mg, 1.65 mmol), and parent compound (1) (354 mg, 1.82 mmol) was prepared. The product was obtained from this reaction and purified by gravity column chromatography using a mixture of 40% ethyl acetate in n-hexane as the eluent. Further purification was performed by thin-layer chromatography using n-hexane as the eluent to obtain a yellow solid. The synthesis yield was 52%. Melting point: 75-78°C. IR (KBr) cm -1 : 2909-2847 (CH sp 3 ), 1574 (C=N), 1512 (C=C Ar), 1451 (CH2), 1343 (CN), 1303-1088 (CO), 810 (C=N). 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 8.1 (d, J = 4.4 Hz, 2H, H-1''); 7.24 (d, J = 4.5 Hz, 2H, H-2''); 3.25 (m, 4H, H-1', H-2'); 2.13 (m, 9H, H-1, H-2); 1.87 (bs, 6H, H-3). 13 ¹¹C-NMR (ppm) (10¹ MHz, CDCl₃) δ: 177.4; 177.1; 149.8; 148.5; 123.7; 40.2; 36.5; 34.3; 31.8; 27.9; 27.2. Calculated molecular weight: 309.1841; Observed molecular weight: 309.1834. <Synthesis and characterization of compound BD-40: 1-(3-methylphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> This compound was prepared by the reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (276 mg, 1.57 mmol), N-methylmorpholine (472 μL, 4.29 mmol), 3-(3-methylphenyl)propionic acid (235 mg, 1.43 mmol), and 1 (333 mg, 1.71 mmol) to obtain the crude product. This was purified by gravity column chromatography using a mixture of 30% ethyl acetate in n-hexane as the eluent. As a further purification step, the product was purified by preparative thin-layer chromatography using n-hexane as the eluent to obtain a colorless gel. The yield of this synthesis reaction was 96%. Melting point: 58-60°C. IR (KBr) cm -1 : 3032(=CH sp 2 Ar), 2909-2847 (CH sp 3 ), 1582 (C=N), 1512 (C=C Ar), 1443 (CH2), 1389 (CH3), 1342 (CN), 1296-1088 (CO). 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 7.39 (t, J = 7.2 Hz, 1H, H-2''); 7.23 (m, 3H, H-1'', H-3'', H-4''); 3.32 (m, 4H, H-1', H-2'); 2.54 (s, 3H, -CH3); 2.27 (m, 9H, H-1, H-2); 2.00 (bs, 6H, H-3). 13 C-NMR (ppm) (10⁻¹ MHz, CDCl₃) δ: 178.3; 177.0; 139.5; 138.2; 129.1; 128.5; 127.3; 125.3; 40.2; 36.5; 34.3; 32.7; 28.7; 28.0; 21.4. Calculated molecular weight: 322.2045 g / mol; Observed molecular weight: 322.2024 g / mol.

[0072] <Synthesis and Characterization of Compound BD-41 1-(4-tert-butylphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> The synthesis was carried out by preparing a reaction mixture consisting of 2-chloro-4,6-dimethoxy-1,3,5-triazine (234 mg, 1.33 mmol), N-methylmorpholine (400 μL, 3.64 mmol), 3-(4-tert-butylphenyl)propionic acid (250 mg, 1.21 mmol), and parent compound (1) (282 mg, 1.45 mmol). From this reaction, a purified product was obtained by gravity column chromatography using a mixture of 10% ethyl acetate in n-hexane as the eluent. As a further purification step, the product was recrystallized from ethanol to obtain a white solid. The yield of this synthesis was 80%. Melting point: 88-91°C. IR (KBr) cm -1 : 2909-2855 (CH sp 3 ), 1574 (C=N), 1504 (C=C Ar), 1450 (CH2), 1358 (CH3), 1343 (CN), 1296-1088 (CO). 1 H-NMR (ppm) (400 MHz. CDCl3) δ: 7.51 (m, 1H, H-3''); 7.22 (d, J = 7.7 Hz, 1H, H-4''); 7.17 (m, 2H, H-1'', H-2''); 3.39 (m, 4H, H-1', H-2'); 2.30 (m, 9H, H-1, H-2); 2.04 (bs, 6H, H-3). 13 C-NMR (ppm) (101 MHz, CDCl3) δ: 177.8; 177.1; 162.9 (d, J = 246.0 Hz, 1C); 142.0 (d, J = 7.3 Hz, 1C); 130.1 (d, J = 8.4 Hz, 1C); 123.9 (d, J = 2.8 Hz, 1C); 115.3 (d, J = 21.3 Hz, 1C); 113.6 (d, J = 21.0 Hz, 1C); 40.2; 36.5; 32.4; 28.3; 28,0. Calculated molecular weight: 364.2515 g / mol; Observed molecular weight: 364.2509.

[0073] <Synthesis and Characterization of BD-42 Compound 1-(3-Fluorophenyl)-2-(3-adamantyl-1,2,4-oxadiazol-5-yl)ethane> Prepared from the reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (mg, mmol), N-methylmorpholine (μL, mmol), 3-(3-fluorophenyl)propionic acid (mg, mmol) and 1 (mg, mmol) to obtain a crude product. This was purified by gravity column chromatography using a mixture of 10% ethyl acetate in n-hexane as the eluent to obtain a colorless gel. The yield of this synthesis was 56%. Melting point: Product in gel state. 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 7.51 (m, 1H, H-3’’). 7.22 (d, J = 7.7 Hz, 1H, H-4’’); 7.17 (m, 2H, H-1’’, H-2’’); 3.39 (m, 4H, H-1’, H-2’); 2.30 (m, 9H, H-1, H-2); 2.04 (bs, 6H, H-3). 13 C-NMR(ppm) (101°MHz. CDCl3) δ: 177.8; 177.1; 162.9 (d, J = 246.0 Hz, 1C); 142.0 (d, J = 7.3 Hz, 1C); 130.1 (d, J = 8.4 Hz, 1C); 123.9 (d, J = 2.8 Hz, 1C); 115.3 (d, J = 21.3 Hz, 1C); 113.6 (d, J = 21.0 Hz, 1C); 40.2; 36.5; 32.4; 32.4; 28.3; 28.0。

[0074] <Synthesis and Characterization of Compound BD-44: 1-(3-Pyridyl)-2-(3-adamantyl-1,2,4-oxadiazol-5-yl)ethane> The synthesis was carried out using a mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (226 mg, 1.29 mmol), N-methylmorpholine (386 μL, 3.51 mmol), 3-(3-pyridyl)propionic acid (177 mg, 1.17 mmol), and parent compound (1) (250 mg, 1.29 mmol). The product was obtained from the mixture and purified by gravity column chromatography using a mixture of 40% ethyl acetate in n-hexane as the eluent. Another purification step was performed by thin-layer chromatography using n-hexane as the eluent, yielding a yellow gel. The yield of this synthesis reaction was 44%. Melting point: Product in gel state. 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 8.61 (bs, 2H, H-2'', H-3''); 7.77 (d, J = 7.7 Hz, 1H, H-4''); 7.43 (s, 1H, H-1''); 3.18 (bs, 4H, H-1', H-2'); 1.99 (m, 9H, H-1, H-2); 1.73 (bs, 6H, H-3). 13C-NMR (ppm) (101 MHz, CDCl3) δ: 177.4; 177.0; 149.1; 147.5; 136.6; 135.3; 123.7; 40.1; 39.6; 36.5; 34.2; 29.7; 27.9.

[0075] <Synthesis and characterization of compound BD-45: 1-(2-pyridyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> The product was prepared from 2-chloro-4,6-dimethoxy-1,3,5-triazine (226 mg, 1.17 mmol), N-methylmorpholine (386 μL, 3.51 mmol), and 3-(2-pyridyl)propionic acid (177 mg). Crude products were obtained and purified by gravity column chromatography using a mixture of 60% ethyl acetate in n-hexane as the eluent. As a further purification step, the product was purified by preparative thin-layer chromatography using n-hexane as the eluent to obtain a yellow gel. The yield of this synthesis reaction was 18%. Melting point: Product in gel state. 1 H-NMR (ppm) (400 MHz, CDCl3) δ: 8.54 (d, J = 7.2 Hz, 1H, H-1''); 7.69 (m, 1H, H-3''); 7.23 (m, 2H, H-2'', H-4''); 3.26 (m, 4H, H-1', H-2'); 1.87 (m, 9H, H-1, H-2); 1.62 (bs, 6H, H-3). 13 C-NMR(ppm) (101 MHz, CDCl3) δ: 177.6; 177.0; 159.6; 147.2; 139.5; 122.9; 40.1; 36.5; 34.2; 32.9; 27.9; 26.0.

[0076] <Synthesis and characterization of compound BD-46: 1-(4-nitrophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane> The crude product was prepared by the reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (226 mg, 1.29 mmol), N-methylmorpholine (386 μL, 3.51 mmol), 3-(4-nitrophenyl)propionic acid (228 mg, 1.17 mmol), and 1 (250 mg, 1.29 mmol). This crude product was purified by gravity column chromatography using a mixture of 20% ethyl acetate in n-hexane as the eluent to obtain a white solid. The yield of this synthesis reaction was 66%. 1H-NMR (ppm) (400 MHz, CDCl3) δ: 8.00 (d, J = 8.6 Hz, 2H, H-1''); 7.22 (d, J = 8.5°Hz, 2H, H-2''); 3.08 (m, 4H, H-1', H-2'); 1.89 (m, 9H, H-1, H-2); 1.63 (bs, 6H, H-3). 13 C-NMR (ppm) (101 MHz. CDCl3) δ: 177.3; 177.1; 147.0; 146.9; 129.3; 123.9; 40.2; 36.5; 34.3; 32.3; 27.9; 27.8.

[0077] <Example 2: Inhibitory and selective effects of compound of formula (I) on the activity of enzyme 11β-HSD1> In this example, we present a biological activity assay to determine the inhibitory effect of compounds of formula (I) on the enzyme 11β-HSD1 dehydrogenase, and how these compounds specifically inhibit the enzyme's oxidase (dehydrogenase) activity and its selectivity for isoforms 1 and 2 (11β-HSD2).

[0078] The biological activity assay is performed by determining the 50% inhibitory concentration (IC50) of cortisol production relative to a control when recombinant enzyme 11β-HSD1 (Cayman Chemical, MI, USA; Item No. 10007815) is exposed to different compounds.

[0079] <Determination of 11β-HSD1 reductase activity> First, stock solutions of the compound were prepared in DMSO at a concentration of 10 μM, and their serial dilutions were prepared to determine efficacy curves.

[0080] Recombinant 11β-HSD1 enzyme (Cayman Chemical, MI, USA; Item No. 10007815) was prepared at different dilutions in 20 mM Tris buffer, 5 mM EDTA, pH 6.0 (Tris buffer).

[0081] First, the enzyme concentration to be used in the assay to evaluate the biological activity of the compound was determined. A cortisol kit product (Cisbio, MA, USA; catalog No. 62 CRTPEG) was used for this purpose.

[0082] The protocol involved preparing the reaction buffer and adding 266 nM cortisone and 333 μM NADPH in Tris buffer. This reaction buffer was then added to the wells of an HTRF (Homogeneous Time Resolved Fluorescence) reaction plate in a 4:1 ratio along with the enzyme, and incubated at 37°C for 2 hours. For the control wells, two wells containing Tris buffer were added without the compound.

[0083] After incubation time, the reagents from the cortisol kit, cortisol d2 and cortisol cryptotate in sample ratios, and cortisol d2 and cortisol cryptotate in a 2:1:1 ratio were added in amounts according to the well sizes indicated by the supplier (for the kit's negative control, cortisol d2 was replaced with the kit's reconstitution buffer). The reaction mixture was incubated at room temperature for 1 hour, after which fluorescence was read at 665 and 620 nm.

[0084] Once the appropriate enzyme concentration was determined, the cortisol kit protocol was continued to determine the efficacy curve of the compound. As previously done, plates for HTRF were prepared, and reaction buffer, recombinant 11β-HSD1 enzyme, and the compound to be assayed were added to each well in a 3:1:1 ratio. The plates were then incubated at 37°C for 2 hours.

[0085] After incubation time, the reagents from the cortisol kit, cortisol d2 and cortisol cryptotate, were added, and the mixture was incubated again at room temperature for 1 hour. Finally, the fluorescence of each well was determined at 665 and 620 nm.

[0086] <Measurement of 11β-HSD1 oxidase activity> The activity of 11β-HSD1 oxidase is measured by determining the concentration of cortisone produced in the reaction in the presence and absence of the compound. A cortisol kit (Cisbio) product was used for this purpose.

[0087] For analysis, the compound was reconstituted in DMSO at a concentration of 10 mM in stock, from which serial dilutions for efficacy curves were prepared.

[0088] Recombinant 11β-HSD1 enzyme dilutions were prepared in 20 mM Tris buffer, 5 mM EDTA, and pH 6.0 (Tris buffer).

[0089] First, the enzyme concentration to be used was determined. For this purpose, plates for HTRF were prepared using Tris buffer containing 100 nM cortisol and 200 μM NADP+. These were added to the wells of the HTRF plate along with the enzyme in a 4:1 ratio, and incubated at 37°C for 2 hours. After this time, the reagents from the cortisol kit, cortisol d2 and cortisol cryptotate in sample ratios, and cortisol d2 and cortisol cryptotate in a 2:1:1 ratio were added, and this new reaction mixture was incubated at room temperature for 1 hour. Subsequently, fluorescence was measured at 665 and 620 nm.

[0090] After determining the appropriate enzyme concentration, the cortisol kit protocol was followed to determine the efficacy curve of the compound. The HRTF plate was prepared again, and the reaction buffer, recombinant 11β-HSD1 enzyme, and compound were added to each well in a 3:1:1 ratio. The plate was incubated at 37°C for 2 hours. After incubation, the cortisol kit reagents, cortisol d2, and cortisol cryptotate were added as described above. These were then incubated at room temperature for 1 hour, and finally, fluorescence at 665 and 620 nm was read.

[0091] <Measurement of 11β-HSD2 oxidase activity> The concentration of cortisone produced during the reaction was measured using a cortisol kit (Cisbio) product, with or without the presence of the compound, to evaluate the activity of 11β-HSD2 oxidase.

[0092] As in the assay already described, the compound is reconstituted in DMSO to a 10 mM stock, followed by serial dilutions to determine the efficacy curve.

[0093] Compound IC 50 To measure this, a model of human liver microsome donor (BioReclamationIVT Inc.) prepared in Tris buffer 20 mM EDTA 5 mM pH 6.0 (Tris buffer) was used.

[0094] To perform the assay, use Tris buffer, 100 nM cortisol, and 200 μM NAD. + An HTRF plate containing the enzymes was prepared. The enzymes were added to the corresponding wells in a 4:1 ratio and incubated at 37°C for 2 hours. For the kit control, only Tris buffer was added to the two wells.

[0095] After incubation time, the cortisol kit reagents, cortisol d2 and cortisol cryptotate in sample ratios of 2:1:1 were added. For the negative control, cortisol d2 was replaced with the kit's reconstitution buffer in several wells. The plates were incubated at room temperature for 1 hour, after which readings were taken at 665 and 620 nm.

[0096] Once the enzyme concentration to be used is determined, the cortisol kit protocol is followed to determine the efficacy curve of the compound. For this purpose, a reaction buffer was prepared, and then, in a plate for HTRF, the reaction buffer, microsomes at a concentration of 5 mg / mL, and the compound in a 3:1:1 ratio were added to each well, respectively. For the reaction control, a reaction buffer without cortisol and without the compound was included as the negative control. For the positive control, no compound was added, and for the kit control, only the reaction buffer was added to the negative control well and the positive control well.

[0097] After incubating the plate for 2 hours, add the cortisol kit reagents, cortisol d2 and cortisol cryptotate, to the corresponding wells as described above. Then, incubate them at room temperature for 1 hour and finally read the fluorescence at 665 and 620 nm.

[0098] The results shown in Table 1 were obtained from the assays already described.

[0099] [Table 1]

[0100] <Example 3: Measurement of the biopharmaceutical properties of compounds of formula (I), BD-40, and BD-44> The examples herein present the results of measurements of permeability on BD-40 and BD-44 monolayers, solubility of compounds of formula (I)BD-40, and binding ability of BD-40 compounds to plasma proteins.

[0101] Prior to these analyses, analytical methods for detecting and quantifying BD-40 and BD-44 compounds were standardized. For this purpose, analytical methods for BD-40 and BD-44 compounds were developed using tandem uHPLC-MS / MS (Triple Quad 4500, AB Sciex Instruments).

[0102] The ionization parameters were optimized by directly injecting a 1 μg / mL solution into a 50:50 acetonitrile (ACN) / water mixture (1 mL / min). These parameters for ionization are shown in the following table (Table 2):

[0103] [Table 2]

[0104] After obtaining optimal ionization parameters, it was necessary to optimize the fragmentation parameters for each compound; for this purpose, the mass spectrometer was operated in multiple reaction monitoring (MRM) and positive mode. For quantification, transition phases of 322,976 / 135,100 (BD40), 310,080 / 135,100 (BD44), 210,061 / 193,200 (minoxidil), and 267,072 / 145,100 (atenolol) were used. The MRM and quantification fragment parameters for each compound are listed in Table 3, where minoxidil and atenolol are also included as markers.

[0105] [Table 3]

[0106] After measuring the parameters described above, chromatographic analysis was performed. For this purpose, an Ekspert ultraLC 100-XL instrument (AB Sciex Instruments) equipped with an autosampler thermostat and column oven was used. A C18 column (Inertsil OSD-4, 3 μm, 2.1 × 100 mm) was used, with an injection volume of 10 μL, a flow rate of 0.5 mL / min, and a column temperature of 40 °C. The mobile phases were 5% water 10 mM ammonium formate pH 5 in ACN (A) and 5% ACN 10 mM ammonium formate in water (B). Table 4 shows the elution gradient for each compound.

[0107] [Table 4]

[0108] The presented methods were partially validated for this purpose; specificity, range, linearity, precision, and accuracy were evaluated. To carry out this evaluation, standard solutions of each compound (BD-40 and BD-44) were prepared in two embodiments at concentrations ranging from 0.1 to 1000 ppb. In the first embodiment, calibration curves were prepared for each compound, while the second embodiment included standard solutions of the compounds (BD-40 and BD-44) plus markers minoxidil and atenolol. The solutions were evaluated in three replicates.

[0109] These methods have been shown to be specific to each compound, and at least 10 3 The results demonstrated a linear range of twice the normal range, a coefficient of determination (R²) of at least 0.984, a coefficient of variation of 1.6% or less for each concentration and each drug, and a precision exceeding 93%.

[0110] <Permeability analysis of monolayers of compounds (I), BD-40, and BD-44).> In this assay, Madin-Darby Canine Kidney (MDCK) cells were stably transfected with the gene encoding human P-glycoprotein (hMDR1). These cells were cultured in glucose-rich DMEM medium (Dulbecco's Modified Eagle's medium) and supplemented with 10% fetal bovine serum, 1% 5 mM pyruvate, 1% non-essential amino acid solution x5, 20,000 IU / mL penicillin G, and 20,000 IU / mL streptomycin. The culture was maintained at 37°C, 90% relative humidity, and 5% CO2. These cells were seeded onto sterile plates on day 4 of growth, or until 90% confluence was reached.

[0111] Ten days before conducting the transport analysis, the cells were placed in Transwells® inserts (1.12 cm²) at a density of 60,000 cells / cm². 2Cells were seeded. The monolayer was replenished with fresh medium every two days. On the day of analysis, the cells were washed three times (both compartments) at 37°C with Hanks Balanced Salt Solution transport buffer, HBSS pH 6.8. They were then incubated with 500 μL of 10 μM compound solution in the presence of markers minoxidil (10 μM) and atenolol (10 μM) in the apical compartment and with 1.5 mL of buffer in the basal outer compartment (experiment A and B, n=3). In parallel, experiment BA was performed (1.5 mL of donor solution in the basal outer compartment and 0.5 mL of buffer in the apical compartment). The monolayer was incubated at 37°C for 2 hours with agitation (50 rpm). Furthermore, this assay was performed in the presence of the Pgp inhibitor Elacrider (5 μM). After agitation, the insert was removed, the compartments were sampled, and the cells were transfected into HPLC vials by diluting these samples by mobile phase chromatography. These samples were kept at -20°C until the time of analysis. The mass balance of each compound remained above 80% at all times.

[0112] The bidirectional transport of each compound was parameterized according to equation (1) as apparent permeability (Papp) from the intercellular flux value based on Fick's first law. Papp = (dM_R) / (A·dT·C_D) (1) Here, dMR corresponds to the amount of compound in the receptor compartment at time t (nmol), and A is the area of ​​the monolayer (cm²). 2 ) where dT is the duration of the test (s) and CD is the donor concentration at time 0 (μM). For each compound, the efflux ratio (ER) was obtained according to formula (2). ER=[Papp]^(BA) / [Papp]^(AB) (2) In this formula, PappB-A represents the apparent permeability of the compound in the direction of secretion, and PappA-B represents the apparent permeability of the compound in the direction of absorption. Since ER > 2 in the absence of elacrida and similar to 1 in the presence of elacrida, activated pgP-mediated secretion is confirmed. Table 5 shows the PappA-B and ER values ​​for BD-40 and BD-44.

[0113] [Table 5]

[0114] Papp values ​​for BD-40 and BD-44 were higher than those for the high permeability marker minoxidil (p<0.01). The Papp for the integrity marker atenolol was less than 0.5 × 10⁻⁶ cm / s. Since the ER value was less than 2 and was not affected by the presence of the inhibitor pgP elacridor, it can be ruled out that BD-40 and BD-44 are P-glycoprotein substrates.

[0115] <Solubility of the BD-40 compound of formula (I).> To study the solubility of BD-40 in the gastrointestinal tract over a range of pH and temperature, flasks containing adjustable buffers at pH 1.2, 4.5, and 6.8 were used. A 100 mM stock solution was prepared in DMSO and added to the buffer in predetermined volumes until turbidity was observed. These solutions were prepared in triplicates at final DMSO concentrations of 0.5–5.0% V / V for each buffer and incubated at 37°C for 48 hours with vigorous stirring. They were then incubated for another 48 hours without stirring. The samples were centrifuged, and the supernatant was diluted by mobile phase chromatography and analyzed by μHPLC-Ms / Ms. Solubility values ​​at each pH were obtained from the linear solubility section relative to %DMSO. Table 6 shows the water solubility of BD-40 in the pH range of 1.2–6.8.

[0116] [Table 6]

[0117] <Analysis of the plasma protein binding ability of the BD-40 compound of formula (I).> To conduct this study, we used a commercially available Transil XL PPB Binding Kit, v2, Sovicell, as recommended by the manufacturer.

[0118] The results showed that the plasma protein binding rate of BD-40 was 98.3 ± 1.9%.

[0119] By measuring the plasma protein binding of a drug, its efficacy can be revealed. When bound to plasma proteins, the drug can pass through the cell membrane to reach its therapeutic target. Furthermore, less drug is lost through excretion, allowing the effective therapeutic dose of the compound to reach its target. In this case, the BD-40 compound of formula (I) shows a high efficacy percentage and less drug loss.

[0120] <Example 4: In vivo assay using BD-40 and BD-44 compounds of formula (I).> Male C57BL / 6J mice, approximately 9–12 weeks old, were used for in vivo evaluation of BD-40 and BD-44 compounds. The mice were provided by the Animal Division of the Science & Life Foundation.

[0121] The animals were classified according to weight and divided into the following groups (Table 7):

[0122] [Table 7]

[0123] Solutions containing the dosage doses of BD-40 and BD-44 were formulated in a vehicle containing 30% dimethyl sulfoxide (DMSO), 20% Kolliphor, and 50% PBS at a concentration of 1 mg / mL. A 0.4 mg / mL dilution of this solution was then prepared for intravenous administration.

[0124] For intravenous (IV) administration, mice were administered each compound, then divided into three groups and euthanized at 5, 10, 15, 30, 60, 120, 240, 260, 480, and 1440 minutes. For oral (VO) administration, mice were divided into three groups and euthanized at 15, 30, 60, 120, 240, 260, 480, and 1440 minutes. Mice that had not been administered the compound were used to obtain a zero-time assay.

[0125] Whole blood was obtained from each animal (in EDTA-containing microtubes). These samples were centrifuged at 9000g at 4°C for 5 minutes to obtain plasma. The plasma was stored at -80°C.

[0126] Furthermore, organs such as the brain, liver, muscles, epididymal fat, heart, and kidneys were obtained from the animals. The animals were frozen in liquid nitrogen and stored at -80°C.

[0127] Plasma samples and brain, liver, epididymal fat, and muscle (tissue) samples were analyzed. 2X volume of water (weight / volume) was added to the tissue samples, while 4X volume of water (weight / volume) was added to the muscle mixture. These were then homogenized using a Bullet Blender (Next Advance, USA).

[0128] All samples were analyzed as single points by LC-MS / MS according to the analytical method already standardized and presented in Example 3.

[0129] First, efficacy curves were developed. For this purpose, control, plasma, and organ samples were prepared by adding 180 μL of cold acetonitrile to each, then vortexing for 15 seconds, and centrifuging at 6100 g for 30 seconds at 4°C. The supernatant obtained from this procedure was diluted with 0.2% formic acid in twice the volume of water and transferred to vials suitable for injection into LC-MS / MS.

[0130] The status of the LC-MS / MS analysis is: HPLC: Eksigent UltraLC 100 Autosampler: Eksigent UltraLC 100-XL at RT Mobile phase: A - 0.1% formic acid in water; B - 0.1% formic acid in acetonitrile.

[0131] Column: YMC Triart 1.9μm, 2.0×50 mm Injection volume: 2 μL Gradient: 5% of B for 0.25 min → 5 - 95% of B for 0.75 min → 95% of B for 2 min → 95 - 5% of B for 0.25 min → 5% of B for 0.25 min Flow rate: 0.6 mL / min Mass spectrometer: Applied Biosystems / SCIEX QTRAP 4500 Interface: Turbo Spray (ESI) at 600 °C Software: Analyte.

[0132] For both compounds, analysis was performed in positive mode. For BD - 40, the parent ion 323.4 [M + 1] and product ion 135.2 [M + 1] were detected, and for BD - 44, the parent ion 310.4 [M + 1] and product ion 135.2 [M + 1] were detected.

[0133] a) Pharmacokinetic analysis results of BD - 40 <Analysis of BD - 40 compound plasma samples> The results obtained for the pharmacokinetic parameters of BD - 40 in plasma are summarized in Table 8. The average time (hr) when the drug was administered intravenously was 3.30, and when administered orally was 0.864 hours.

[0134]

Table 8

[0135] The detection and analysis of pharmacokinetic parameters of the BD-40 compound were also performed in the brain, liver, adipose tissue, and muscle. The BD-40 compound was observed to have good bioavailability and could be detected in different tissues of the evaluated organs (brain, liver, adipose tissue, and muscle) when administered both orally and intravenously (Figures 1 and 2).

[0136] b) Results of pharmacokinetic analysis of BD-44 The results obtained regarding the pharmacokinetic parameters of BD-44 are summarized in Table 9. The mean time to drug elimination (hrs) was 1.02 when the drug was administered intravenously and 1.05 when the drug was administered orally. The BD-44 compound was detected up to 6 hours after administration in both intravenous and oral administrations (Figure 3).

[0137] The low apparent availability of BD-44 was observed in plasma and not detected in assayed tissues, which corresponds to an initial analysis that does not take drug administration regimens into account.

[0138] [Table 9]

[0139] <References> Kadmiel M. and Cidlowski JA. (2013.) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci.; 34(9):518-30). Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM. (2003). Transgenic ampli-fication of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest°2003; 112: 83-90). Livingstone DEW, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR. (2000). Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese zucker rats. Endocrinology 2000; 141: 560-3. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS. (2004). 118-Hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response.°Endocrine Reviews; 25: 831-66). Wake DJ y Walker BR (2004). 11-beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Mol Cell Endrocrinol 215(1-2):45-54. Walker DJ y Walker B. R (2006). Cortisol-cause and cure for metabolic syndrome?. Diabet Med 23(12): 1281-1288. [Brief explanation of the drawing]

[0140] [Figure 1] BD40 (nM) levels detected in plasma and other tissues at IV doses (2 mg / kg) over different time periods. [Figure 2] BD40 (nM) levels detected in plasma and other tissues at an oral dose (10 mg / kg) over different periods. [Figure 3] A graph summarizing the levels of BD-44 compound detected in plasma at different time points, IV dose (2 mg / kg), and oral dose (10 mg / kg).

Claims

1. When L1 is CH or a nitrogen atom, and L1 is a nitrogen atom, L1 is different from L3. L2 is either a carbon or nitrogen atom, and when L2 is a nitrogen atom, R1 does not exist. L3 is either a carbon or nitrogen atom, and when L3 is a nitrogen atom, R2 does not exist. R1, R2, and R3 are independently hydrogen atoms, F, Br, Cl, and NO. ２ , straight chain or branched C １－４ Selected from alkyl groups or OR groups, where R is H or linear or branched C. １－４ A compound of formula (I) characterized by being an alkyl group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. 【Chemistry 1】

2. The aforementioned compounds are 1-phenyl-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-31), 1-(4-methoxyphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-32), 1-(4-chlorophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-33), and 1-(4-fluorophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-34). , 1-(4-bromophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-35), 1-(4-methylphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-36), 1-(4-hydroxyphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-37), 1-(3-methoxyphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD- 38), 1-(4-pyridyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-39), 1-(3-methylphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-40), 1-(4-tert-butylphenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-41), 1-(3-fluorophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane ( A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, characterized in that it is BD-42), 1-(3-pyridyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-44), 1-(2-pyridyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-45), or 1-(4-nitrophenyl)-2-(3-adamantyl-1,2,4-oxadiazole-5-yl)ethane (BD-46).

3. A pharmaceutical composition characterized by comprising a therapeutically effective amount of the compound of formula (I) described in claims 1 and 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in a pharmaceutically acceptable solvent.

4. Use of a compound of formula (I) according to claims 1 and 2, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the preparation of a drug used for the treatment of one or both of conditions and diseases, including hypertension, obesity, dyslipidemia, type 2 diabetes, insulin resistance, glaucoma, metabolic syndrome, cognitive impairment, osteoporosis, immune disorders, and depression.

5. Use of the pharmaceutical composition according to claim 3 in the preparation of a drug used for the treatment of one or both of conditions and diseases, including hypertension, obesity, dyslipidemia, type 2 diabetes, insulin resistance, glaucoma, metabolic syndrome, cognitive impairment, osteoporosis, immune disorders, and depression.

6. A process for preparing the compounds described in claims 1 and 2, The aforementioned process consists of the following steps: a) A step of preparing a mixture of hydroxylamine hydrochloride and sodium carbonate in ethanol and glycerol, and stirring it overnight at room temperature. b) A step of reacting the mixture obtained in a) with 1-cyanoadamantane and aluminum chloride in ethanol, c) Stirring the obtained white suspension under reflux conditions for 10 hours. d) After 10 hours, the residual ethanol is removed by vacuum filtration, the residue is partitioned with water and dichloromethane, and the aqueous phase is further extracted with dichloromethane. e) Wash the obtained organic phase with brine and dry it with anhydrous sodium sulfate to obtain a white product corresponding to 1-adamantylamidoxime (1). 【Chemistry 2】 f) A step of reacting parent 1-adamantylamidoxime (1) with a 2-chloro-4,6-dimethoxy-1,3,5-triazine compound and N-methylmorpholine in the presence of a propionic acid derivative, or a step of reacting parent 1-adamantylamidoxime (1) with a 2-chloro-4,6-dimethoxy-1,3,5-triazine compound and 1,4-dioxane in the presence of a propionic acid derivative. The propionic acid derivatives correspond to 3-phenylpropionic acid, 3-(4-methoxyphenyl)propionic acid, 3-(4-chlorophenyl)propionic acid, 3-(4-fluorophenyl)propionic acid, 3-(4-bromophenyl)propionic acid, 3-(p-tolyl)propionic acid, 3-(4-hydroxyphenyl)propionic acid, 3-(3-methoxyphenyl)propionic acid, 3-(3-methylphenyl)propionic acid, 3-(4-tert-butylphenyl)propionic acid, 3-(3-fluorophenyl)propionic acid, 3-(2-pyridyl)propionic acid, 3-(3-pyridyl)propionic acid, 3-(4-pyridyl)propionic acid, and 3-(4-nitrophenyl)propionic acid, in the process, A step to purify the product obtained from the reaction in g) f), Includes, A process characterized by the following:

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