A novel benzoxazine benzimidazole derivative, a pharmaceutical composition comprising the same, and a use thereof
A technology of benzimidazole and benzo, which is applied to novel benzoxazine benzimidazole derivatives, pharmaceutical compositions containing the derivatives and the fields of use thereof, and can solve problems such as reducing thermal hyperalgesia pain response and the like
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Embodiment 1
[0220] Example 1: 8-(5-tert-butyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (compound 1a) Preparation
[0221] (1-1) Preparation of ethyl 2-hydroxy-3-nitrobenzoate (compound 3)
[0222] Dissolve 10.0 g (55 mmol) of 2-hydroxy-3-nitrobenzoic acid in 100 mL of ethanol. 2 mL of concentrated hydrochloric acid was added dropwise thereto, and stirred under reflux for 24 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The diluted solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (10.0 g, yield: 86%).
[0223] 1 H NMR (CDCl 3 ) δ: 8.15 (d, 2H, J=8.1Hz), 7.00 (t, 1H, J=8.1Hz), 4.47 (q, 2H, J=7.1Hz), 1.45 (t, 3H, J=7.1Hz)
[0224] (1-2) Preparation o...
Embodiment 2
[0235] Example 2: 8-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxa Preparation of oxazine (compound 1a)
[0236] The steps of Example 1 were repeated, except that 4-trifluoromethylbenzene-1,2-diamine was used to replace 4-tert-butylbenzene-1,2-diamine in (1-5), so that The title compound (5.75 g, yield: 90%) was obtained.
[0237] 1 H NMR (CDCl 3 ) δ: 7.88 (dd, 1H, J=7.9, 1.5Hz), 7.70-7.45 (m, 2H), 7.27 (dd, 1H, J=8.7, 1.8Hz), 6.94 (t, 1H, J=7.8Hz ), 6.70 (dd, 1H, J=7.8, 1.5Hz), 4.53 (t, 2H, J=4.5Hz), 3.55 (t, 2H, J=4.5Hz)
Embodiment 3
[0238] Example 3: 8-(6-Bromo-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 1a) preparation of
[0239] The procedure of Example 1 was repeated except that 4-bromobenzene-1,2-diamine was used instead of 4-tert-butylbenzene-1,2-diamine in (1-5) to obtain the title compound (6.1 g, yield: 92%).
[0240] 1 H NMR (CDCl 3) δ: 7.89 (dd, 1H, J=7.9, 1.5Hz), 7.79 (s, 1H), 7.50 (s, 1H), 7.35 (dd, 1H, J=8.7, 1.7Hz), 6.94 (t, 1H , J=7.8Hz), 6.70 (dd, 1H, J=7.8, 1.5Hz), 4.54 (t, 2H, J=4.5Hz), 3.57 (t, 2H, J=4.5Hz)
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