Substituted indoles and their use as integrin antagonists
a technology of indole and antagonist, which is applied in the field of substituted indole compounds, can solve the problems of increased mortality, incapacitation, and increased bone fractures
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example 1
3-{5-[3-(2-Pyridylamino)propoxy]indolyl}propanoic acid ammonium salt
[0283]
a). 2-(3-Hydroxypropyl)aminopyridine N-oxide
[0284] A mixture of 2-chloropyridine-N-oxide hydrochloride (3.32 g, 20 mmol), 3-amino-1-propanol (3.06 mL, 40 mmol), NaHCO3 (8.4 g, 100 mmol) in tert-amyl alcohol (20 mL) was heated to reflux. After stirring overnight, the reaction mixture was cooled, diluted with methylene chloride (100 mL), and suction filtered to remove the insoluble materials. The filtrate was concentrated and reconcentrated from methylene chloride twice. The residue was recrystallized from ethyl acetate and hexane, collected by filtration, washed with ethyl acetate, and dried under high vacuum to give the title compound as a pale yellow solid (3.2 g, 95%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (d, J=6.5 Hz, 1H), 7.32 (br s, 1H), 7.21 (t, J=8.6 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.53 (t, J=6.7 Hz, 1H), 3.75 (t, J=5.8 Hz, 2H), 3.47 (q, J=6.2 Hz, 2H), 1.86 (t, J=6.0 Hz, 2H).
b). 2-(3-Hydroxypropyl)aminopy...
example 2
3-{5-[3-(2-Pyridylamino)propoxy]indolyl}acetic acid ammonium salt
[0290]
a). Methyl 2-(5-benzyloxyindolyl)acetate
[0291] 5-Benzyloxyindole (0.80 g, 3.58 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL) and treated with 60% sodium hydride in mineral oil (0.36 g, 9.00 mmol) at ambient temperature. After 2 h, ethyl bromoacetate (0.45 mL, 4.06 mmol) was added, the reaction stirred for 6 h, and additional sodium hydride (0.36 g, 9.00 mmol) was added. The reaction stirred for 3 days, the N,N-dimethylformamide was removed in vacuo, and the residue was dissolved in methylene chloride. The resulting solution washed with 10% aqueous HCl, water, and brine, dried over anhydrous sodium sulfate, and filtered. The evaporated filtrate was then dissolved in N,N-dimethylformamide (20 mL) and treated with cesium carbonate (1.57 g, 4.80 mmol) and iodomethane (0.30 mL, 3.75 mmol) at ambient temperature for 18 h. The reaction was concentrated in vacuo, the crude product dissolved in methylen...
example 3
3-{2-Methyl-5-[3-(2-pyridylamino)propoxy]indolyl}propanoic acid sodium salt
[0295]
a). 3-(5-Methoxy-2-methylindolyl)propanoic acid
[0296] 5-Methoxy-2-methylindole (0.50 g, 3.10 mmol) was dissolved in anhydrous N,N-dimethylformamide (25 mL) and treated with 60% sodium hydride in mineral oil (0.19 g, 4.70 mmol) at ambient temperature for 2 h. Ethyl 3-bromopropionate (0.60 mL, 4.20 mmol) was added, the reaction stirred for 3.5 h, treated with additional sodium hydride (0.20 g, 4.88 mmol), and stirred another 24 h. After concentration in vacuo, the crude product was dissolved in methylene chloride, the solution washed with dilute aqueous HCl and brine, dried over anhydrous sodium sulfate, and filtered. The evaporated filtrate was purified by flash column chromatography (1:1 hexane:ethyl acetate as eluant) giving the title compound as a yellow-orange solid (0.56 g, 77%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, 1H, J=8.8 Hz), 7.00 (d, 1H, J=2.4 Hz), 6.80 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.17 (s, 1H...
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