New 2-pyridylethylamines with dopaminergic activity: Synthesis and radioligand-binding evaluation

An improved synthesis of 5,6,7,8‐tetrahydro‐1,7‐naphthyridine ‐ a conformationally‐restricted analog of 2‐(3‐pyridyl)ethylamine

“…The resulting oil was purified by elution through a pad of silica gel (400 g) employing 5% ethyl acetate/hexanes to afford the title compound as a yellow oil, 26.6 g (92%). 1 …”

“…Chromatography through a pad of silica gel (300 g) employing a gradient of 5% to 20% ethyl acetate/hexanes afforded the title compound as a golden oil, 11.5 g (65%). 1 A slurry of 1-benzyl-4-(2-[1,3]dioxolan-2-yl-ethyl)-3-piperidone (5) (0.73 g, 2.5 mmol) and hydroxylamine hydrochloride (1.8 g, 25 mmol) in anhydrous ethanol (25 mL) was stirred at 70°C for 16 hours. The resulting brown solution was cooled, concentrated in vacuo, diluted with half-saturated aqueous sodium carbonate and extracted twice with dichloromethane.…”

“…The resulting brown oil was chromatographed on a Biotage Flash 40S eluting with a gradient of 0%-1.5% methanol in dichloromethane to afford the title compound as a golden oil, 0.19 g (34%). 1 A slurry 7-benzyl-5,6,7,8-tetrahydro-1,7-naphthyridine (6) (170 mg, 0.76 mmol) and 10% palladium-on-carbon (0.85 mg) in methanol (4 mL)/4 N HCl in dioxane (0.8 mL) was treated with 50 p.s.i. of hydrogen on a Parr apparatus for 6 hours.…”

“…Of particular interest is the suggestion that 1 is bioisosteric to the 3-hydroxyphenylethylamine pharmacophore found in many dopamine agonists [1]. This replacement of 3-hydroxyphenyl with pyridyl could potentially lead to agents with improved pharmacokinetic properties, given the low bioavailability and short in vivo half-lives associated with the former functionality.…”

“…The 2-(3-pyridyl)ethylamine pharmacophore (1) has been documented to possess a range of pharmacological activities, including potent binding to members of the dopaminergic [1] and cholinergic [2] receptor families. Of particular interest is the suggestion that 1 is bioisosteric to the 3-hydroxyphenylethylamine pharmacophore found in many dopamine agonists [1].…”