Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors
A drug, selected technology, applied in the field of composition of diseases or diseases, can solve problems such as tolerance problems
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Embodiment 1
[0469] (3-{[3,5-bistrifluoromethyl-benzyl)-(2-cyclopropylmethyl-2H-tetrazol-5-yl)-amino]-methyl-}-8-methyl Synthesis of -quinolin-2-yl)-bis-cyclopropylmethyl-amine
[0470] Step (i): Synthesis of 2-chloro-8-methyl-quinoline-3-carbaldehyde
[0471]
[0472] At 0 °C, DMF (1.22 g, 16.7 mmol) was added to a flask equipped with a drying tube, POCl was added dropwise 3 (7.32 g, 46.7 mmol), while stirring. To this solution was added N-o-tolylacetamide (1.00 g, 6.7 mmol), and the solution was refluxed at 90°C for 6 hours. Distill off excess POCl 3 , water was added to the residue, and it was stirred at room temperature for 10 minutes. The solid was filtered off and dried in vacuo. The crude compound was purified with silica gel (100-200 mesh) using 6% ethyl acetate and petroleum ether to give the product as a yellowish solid (yield: 78%). 1 HNMR (CDCl 3 , 200MHz): δ10.5(s, 1H) 58.71(s, 1H), 7.83-7.79(m, 1H), 7.74-7.70(m, 1H), 7.56-7.49(m, 1H), 2.79(s, 3H); m / z (EI-MS): 206 ...
Embodiment 2
[0492] (3-{[3,5-bis-trifluoromethyl-benzyl)-(2-cyclopentyl-2H-tetrazol-5-yl)-amino]-methyl-}-8-methyl- Synthesis of quinolin-2-yl)-bis-cyclopropylmethyl-amine
[0493]
[0494] (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl )-bis-cyclopropylmethyl-amine (0.4 g, 0.679 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were added to 25 mL of RB. 4 mL of DMF was added thereto, and the reaction mixture was stirred at room temperature for 0.5 hr. Cyclopentyl bromide (0.12 g, 0.814 mmol) was then added dropwise. The reaction temperature was raised to 60°C and stirring was continued for an additional 2 hours. The reaction mixture was cooled to room temperature, ice was added, extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide the crude product, which was purified on silica gel (100-200 mesh) using 4% ethyl acetate and petroleum ...
Embodiment 3
[0496] (3-{[3,5-bistrifluoromethyl-benzyl)-(2-cyclohexyl-2H-tetrazol-5-yl)-amino]-methyl-}-8-methyl-quinoline Synthesis of -2-yl)-bis-cyclopropylmethyl-amine
[0497]
[0498] (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl )-bis-cyclopropylmethyl-amine (0.275 g, 0.46 mmol) and potassium carbonate (0.19 g, 1.40 mmol) were added to 25 mL of RB. 4 mL of DMF was added thereto, and the reaction mixture was stirred at room temperature for 0.5 hr. Cyclohexyl bromide (0.09 g, 0.552 mmol) was then added dropwise. The reaction temperature was raised to 60°C and stirring was continued for an additional 2 hours. The reaction mixture was cooled to room temperature, ice was added, extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to provide a crude product which was purified on silica gel (100-200 mesh) using 4% ethyl acetate and petroleum ether...
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