Heterocyclyl compounds as histamine H3 receptor ligands
A compound, compound phase technology, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc.
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Embodiment 1
[0176] Example 1: 1-[2-(1-cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl] - Preparation of propan-1-one tartrate
[0177] Step (i): tert-butyl 2-(1-cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate Preparation of esters
[0178]1-Cyclobutyl-piperidin-4-ol (1.6 g, 10 mmol) in THF (20 mL) was slowly treated with a cooled and stirred suspension of sodium hydride (0.9 g, 18 mmol) in THF (20 mL) 30 min; the reaction mixture was allowed to stir for 1 h. 2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (3 g, 9 mmol, obtained in Preparation 1) was added dropwise over 15 minutes solution in tetrahydrofuran (30 mL) and the reaction was refluxed for 6 hours. The reaction mass was quenched with ice-cold water, then the product was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water and then brine, then dried over anhydrous sodium sulfate. Organic volat...
Embodiment 2
[0193] Example 2: [2-(4-cyclobutyl-cyclohexyloxy)-4,5,7,8-tetrahydro-thiazolo[5,4-d]azepine Preparation of -6-yl]-cyclopropyl-methanone tartrate
[0194] Step (i): Preparation of 1-cyclopropanoyl-azepan-4-one
[0195] A solution of azepan-4-one (1.75 g, 15.3 mmol) and triethylamine (6.45 mL, 3.1 mmol) in dichloromethane (15 mL) was cooled to 0°C. Cyclopropanoyl chloride (0.17 mL, 1.8 mmol) in dichloromethane (2 mL) was added and the reaction was stirred for 30 minutes. The reaction mass was poured onto ice-cold water, then the product was extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with water and then brine, then dried over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum to obtain the title compound (2.7 g).
[0196] 1 H-NMR (δppm): 0.66-0.69 (4H, m), 1.56-1.57 (1H, m), 1.71-1.75 (1H, m), 1.87-1.89 (1H, m), 2.45-2.49 (1H, m ), 2.59-2.62 (1H, m), 3.57-3.91 (4H, m);
[0197] Mass(m / z): 182(M+H) + .
...
Embodiment 3
[0217] Example 3: Preparation of N-[2-(1-cyclobutyl-piperidin-4-yloxy)-4,5,6,7-tetrahydro-benzothiazol-6-yl]-propionamide
[0218] Step (i): Preparation of 2-bromo-4,5,6,7-tetrahydro-benzothiazol-6-ylamine
[0219] (2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.50 g, 1.5 mmol, obtained in Preparation 2) in dichloromethane (30 mL). The reaction mass was allowed to stir for 4 hours. After the reaction was complete, the material was quenched with ice-cold water, and then the pH was adjusted to 10 by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3 x 50 mL), and the combined organic layers were washed with water and then brine, then dried over anhydrous sodium sulfate. The organic volatiles were evaporated under vacuum to obtain the title compound (0.36 g).
[0220] Mass (m / z): 233.0 (M+H) + , 235.0(M+3H) + .
[0221] Step (ii): Preparation of N-(2-bromo-4,5,6,7-tetrahydro-benzothiazol-6-yl)-pro...
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