Enantiodifferentiation of dihydropyridine PAF antagonists

Novel Antagonists of Platelet-Activating Factor. 1. Synthesis and Structure-Activity Relationships of Benzodiazepine and Benzazepine Derivatives of 2-Methyl-1-phenylimidazo[4,5-c]pyridine

“…A mixture of 4-chloro-3-nitropyridine-CAUTION, skin irritant- (1.02 g, 6.44 mmol) and 4-iodoaniline (1.409 g, 6.44 mmol) in ethanol (20 mL) was stirred at room temperature for 21 h. The solvent was removed under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (3 x 50 mL). The combined organic solutions were dried (MgSO,*) and concentrated under reduced pressure to give an orange solid (950 mg, 43%), mp 137-139 °C, after recrystallization from ethyl acetate: !H NMR (300 MHz, CDC13) <5 6.97 (1H, d, J = 6 Hz), 7.09 (2H, d, J = 9 Hz), 7.84 (2H, d, J = 9 Hz), 8.32 (1H, d, J = 6 Hz), 9.34 (1H, s), 9.61 (1H, br s). This material (1.92 g, 5.63 mmol) was heated with stannous chloride (5.34 g, 28.2 mmol) in ethanol (50 mL) under reflux for 15 min and cooled in ice/water, and excess aqueous potassium hydroxide (40%) was added slowly.…”

“…This material (1.92 g, 5.63 mmol) was heated with stannous chloride (5.34 g, 28.2 mmol) in ethanol (50 mL) under reflux for 15 min and cooled in ice/water, and excess aqueous potassium hydroxide (40%) was added slowly. The product was extracted into ethyl acetate (4 x 100 mL), and the combined extracts were washed with saturated aqueous sodium chloride (50 mL), dried (MgSCh), and concentrated under reduced pressure to give a brown solid, which was purified by flash chromatography (eluting with ethyl acetate/ methanol = 7:1 and then 5:1) to give 3-amino-4-(4-iodophenyl)aminopyridine as a fawn solid (1.174 g, 67%): XH NMR (300 MHz, CDC13) 6 3.39 (2H, br s), 5.80 (1H, br s), 6.88 (2H, d, J = 8 Hz), 7.02 (1H, d, J = 5 Hz), 7.65 (2H, d, J = 8 Hz), 8.01 (1H, d, J = 5 Hz), 8.11 (1H, s).…”

“…A mixture of 3-amino-4-(4-iodophenyl)aminopyridine (311 mg, 1.0 mmol), acetic anhydride (95 uL, 1.0 mmol), and triethyl orthoacetate (920 fih, 5.0 mmol) was heated at reflux under nitrogen for 2 h. The excess reactants were removed under reduced pressure, and the residue was purified by flash chromatography (eluting with ethyl acetate/methanol = 4:1) to give 2-methyl-l-(4-iodophenyl)imidazo[4,5-c]pyridine (3) (244 mg, 73%) as a pale brown solid: mp 180-182 °C; !H NMR (300 MHz, CDCls) <5 2.57 (3H, s), 7.10 (1H, d, J = 5 Hz), 7.14 (2H, d, J = 9 Hz), 7.98 (2H, d, J = 9 Hz), 8.41 (1H, d, J = 5 Hz), 9.07 (1H, s).…”

“…2-Methyl-l-[4-(3,4-dihydro-3-oxo-2-phenyl-3H-pyrazol-5-yl)phenyl]imidazo[4,5-c]pyridine (7). A mixture of compound 4 (350 mg, 1.08 mmol), phenylhydrazine (107 jxL, 1.08 mmol), and powdered anhydrous calcium chloride (100 mg) in dry dichloromethane (2 mL) was stirred at room temperature for 15 h. The mixture was filtered and concentrated under reduced pressure to give a yellow gum (460 mg), which was dissolved in glacial acetic acid (1 mL) and added slowly to concentrated sulfuric acid (2 mL) at room temperature with stirring.…”

Rapid quantification of amlodipine enantiomers in human plasma by LC‐MS/MS: application to a clinical pharmacokinetic study

“…Similar to most other calcium blocking agents of the dihydropyridine class, a racemic mixture of AML is used for therapeutic purposes. However, it has been reported that the vasodilatation effect of AML can be ascribed to its S ‐enantiomer (Kungys et al ., ; Zhang et al ., ; Cooper et al ., ; Abernethy, ; Meredith and Elliott, ; Elliott et al ., ; Reid et al ., ). As reported before, S ‐AML is mostly associated with AML antihypertensive effects, while R ‐AML is thought to be responsible for nitric oxide‐mediated vasodilatation, which is associated with adverse effects, including peripheral edema and facial flushing (Goldman et al ., ; Zhang et al ., ).…”