Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
A technology of unsubstituted compounds, applied in the fields of pharmaceutically acceptable compositions, novel intermediates, and solvates
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preparation example 1
[0101] a) 1) active ingredient 30g
[0102] 2) Lactose 95g
[0103] 3) Corn starch 30g
[0104] 4) Carboxymethyl cellulose 44g
[0105] 5) Magnesium stearate 1g
[0106] 200g / 1000 pieces
[0107] Ingredients 1 to 3 were uniformly blended with water, dried under reduced pressure and then granulated. Ingredients 4 and 5 were mixed well with the granules, and 1000 tablets were compressed with a tablet machine, each containing 30 mg of the active ingredient.
[0108] b) 1) active ingredient 30g
[0109] 2) Calcium phosphate 90g
[0110] 3) Lactose 40g
[0111] 4) Corn starch 35g
[0112] 5) Polyvinylpyrrolidone 3.5g
[0113] 6) Magnesium stearate 1.5g
[0114] 200g / 1000 pieces
[0115] Components 1-4 were uniformly wetted with the aqueous solution of 5, dried under reduced pressure, and then granulated. Ingredient 6 was added, and the granules were compressed into 1000 tablets with a tablet machine, each containing 30 mg of...
Embodiment 1
[0141] Ethyl(E / Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy Acrylate Under a nitrogen atmosphere, triethyl 2-ethoxyphosphonoacetate (W.Grell and H.Machleidt, "Annalen Chemie" 1960, 699, 53) (7.8g, 29.1mmol) in anhydrous tetrahydrofuran (15ml) The solution was added slowly to a stirred suspension of ice-cooled sodium hydride (60% oil dispersion) (1.39 g, 29.1 mmol) in anhydrous THF (5 mL). The mixture was stirred at 0°C for 30 minutes, then 4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (7.5 g, 26.5 mmol ) in anhydrous tetrahydrofuran (20 ml), which was prepared according to the method described in Preparation 1 disclosed in our International Patent Publication No.WO98 / 52946. The mixture was allowed to warm to 25°C and stirred for a further 20 hours. The solvent was evaporated, the residue was suspended in water (100ml) and extracted with ethyl acetate (2x75ml). The combined ethyl acetate layers were washed with water (75ml), brine (50ml),...
Embodiment 2
[0144] (±) Methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate
[0145] The ethyl (E / Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]- A mixture of 2-ethoxyacrylate (8.0 g, 20.0 mmol) and magnesium turnings (9.64 g, 396.7 mmol) in anhydrous methanol (50 mL) was stirred at 25°C for 20 hours. At the end of this time, water (50ml) was added, the pH was adjusted to about 7.0 with 10% aqueous hydrochloric acid, and the solution was extracted with ethyl acetate (2 x 10ml). The combined organic extracts were washed with water (75ml), brine (75ml), dried (Na 2 SO 4 ), filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2:8) as eluent to afford the title compound (5.0 g, 64%) as a gummy liquid.
[0146] 1 H NMR (CDCl 3 , 200MHz): δ1.15(t, J=7.00Hz, 3H), 2.93(d, J=6.64Hz, 2H), 3.23-3.38(composite, 1H), 3.43-3.72(compound, 8H), 3.97(...
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