Cyclourea Compounds as Calcium Channel Blockers
a technology of cyclourea compounds and calcium channels, applied in the field of medicinal chemistry, to achieve the effect of treating, preventing or ameliorating a disorder
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example 1
1-[4,4-Bis(4-fluorophenyl)butyl]-imidazolidin-2-one (3)
[0223]To a suspension of sodium hydride (0.72 g, 18 mmol) in DMF (20.0 mL) was added a solution of imidazolidin-2-one (1) (2.5 g, 30.0 mmol, Aldrich) in DMF (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 45 minutes and then a solution of 4,4-bis(4-fluorophenyl)butyl chloride (2) (5.6 g, 10 mmol) in DMF (10.0 mL) was added. Then the mixture was stirred at 60° C. for 4 hours. After this period, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL×3). The organic layer was dried with anhydrous Na2SO4 and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate / hexane gradient as an eluent to give the title compound 3. MS: m / z 331. 1H NMR (CDCl3): δ 7.16 (m, 4H), 6.96 (t, J=8 Hz, 4H), 4.36 (br, 1H), 3.91 (t, J=8 Hz, 1H), 3.38 (m, 2H), 3.32 (m, 2H), 3.21 (t, J=8 H...
example 2
1-[4,4-Bis(4-fluorophenyl)butyl]-3-(pyridin-2-ylmethyl)imidazolidin-2-one (5)
[0224]To a suspension of sodium hydride (0.06 g, 1.6 mmol) in DMF (1.0 mL) was added a solution of 1-[4,4-bis(4-fluorophenyl)butyl]imidazolidin-2-one (3) (0.2 g, 0.6 mmol) in DMF (1.0 mL) at room temperature. The resulting mixture was stirred at 70° C. for 1.0 hour and cooled to room temperature before adding a solution of compound 4 (0.16 g, 1 mmol, Aldrich) in DMF (0.5 mL). The resulting reaction mixture was stirred at 70° C. for 4 hours. After this period, the mixture was cooled to room temperature and quenched with water (5.0 mL). The mixture was extracted with chloroform (10 mL×2). The organic layer was dried (Na2SO4) and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate / hexane gradient as an eluent to give 65 mg of the title compound 5 as a clear oil. MS: m / z 422. NMR (400 MHz, CDCl3): δ 8.56-8.49 (m, 1H), 7.66-7.59 (m, 1H), 7.34-7.26 (m, 2...
example 3
2-[4,4-Bis(4-fluorophenyl)butyl]-4-benzyloxycarbonyl-2,4-diaza-bicyclo[3.1.0]hexan-3-one (8) 2-[4,4-Bis(4-fluorophenyl)butyl]-2,4-diaza-bicyclo[3.1.0]hexan-3-one (9)
[0229]3-oxo-2,4-diaza-bicyclo[3,1,0]hexane-2-carboxylic acid benzyl ester (6) (0.78 g, 3.34 mmol, Rare Chemicals GmbH) was dissolved in DMF (10.0 mL). Potassium hydroxide (0.28 g, 5.0 mmol) was added to the solution followed by compound 7 (1.37 g, 3.67 mmol). The resulting mixture was stirred at room temperature for 5 hours. Then the mixture was diluted with water (10.0 mL) and extracted with methylene chloride (50 mL×3). The organic layer was dried with anhydrous Na2SO4 and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate / methylene chloride gradient as an eluent to give 1.13 g of the title compound 8 and 90 mg of the title compound 9. MS for compound 8: m / z 477. MS for compound 9: m / z 343.
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