Levorotatory meptazinol derivative, preparation method and pharmaceutical application thereof
A pharmacy and compound technology, applied in the directions of drug combination, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve the problems of weakened curative effect, cure the symptoms but not the root cause, etc., and achieve the effect of high therapeutic index and small toxic and side effects.
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Embodiment 1
[0072] Example 1 N-[2-(1H-indol-3-yl)ethyl]-8-bromooctylamide
[0073] 0.22 g (1.0 mmol) of 8-bromooctanoic acid was dissolved in 20 mL of anhydrous CH 2 C1 2 Add EDC 0.19g (1.0mmol), DMAP 0.12g (1.0mmol), stir evenly, add tryptamine 0.16g (1.0mmol), stir and react at room temperature for 2 hours, a white solid precipitates, filter, add 1N to the filtrate Wash with 10 mL of hydrochloric acid, then with 10 mL of water, and wash with anhydrous Na 2 SO 4 dry. Filtration, concentration, silica gel column chromatography (CH 2 C1 2 ~5%EtOH / CH 2 C1 2 ) to obtain brown oily substance 0.25g, yield 68.4%.
[0074] 1 HNMR (CDCl 3 ): 8.30 (s, 1H, NH, heavy water exchange disappears), 7.61 (d, J = 8Hz, 1H, ArH), 7.39 (d, J = 8Hz, 1H, ArH), 7.21 (t, J = 7Hz, 1H , ArH), 7.13(t, J=7Hz, 1H, ArH), 7.03(s, 1H, ArH), 5.56(s, 1H, NHCO, heavy water exchange disappeared), 3.61(dd, J=6.1Hz, 2H, N-CH 2 ), 3.39 (t, J=6.7Hz, 2H, BrCH 2 ), 2.98(t, J=6.5Hz, 2H, indoL-CH 2 ), 2.09(t, J=7Hz, ...
Embodiment 7
[0079] Example 7 5-[(1′,2′-dithiolane)-3-yl]-N-(3-chloropropyl)-pentanamide
[0080]Dissolve 0.65 g (5.00 mmol) of 3-chloropropylamine hydrochloride in 30 mL of anhydrous CH 2 C1 2 Add EDC 1.2g (6.26mmol), DMAP 2.0g (16.3mmol), stir well, add lipoic acid 1.05g (5.09mmol), vacuumize, fill with nitrogen three times, under nitrogen protection, stir at room temperature for 12-24 hours, washed with 10 mL of 1N hydrochloric acid, washed twice with 10 mL of water, and washed with anhydrous Na 2 SO 4 dry. Filter and concentrate to obtain 0.99 g of a grass-green oil. Silica gel column chromatography (eluent: ethyl acetate) gave 360.51 g of a light yellow oily substance, with a yield of 36.2%.
[0081] 1 HNMR (CDCl 3 ): 6.01(s, 1H, NHCO, heavy water exchange disappears), 3.55(t, J=6.3Hz, 2H, CL-CH 2 ), 3.54-3.52 (m, 1H, S-CH 2 ), 3.37 (dd, J 1 =12.7Hz,J 2 =6.3Hz, 2H, N-CH 2 ), 3.18-3.05 (m, 2H, S-CH 2 ), 2.47-2.39 (m, 1H, SCH 2 CH 2 ), 2.16(t, J=7.4Hz, 2H, CH 2 CO), 2.00...
Embodiment 8
[0083] Example 8 6-[(S)-3-Ethyl-3-(3′-hydroxyphenyl)-azepan-1-yl]-N-[2-(1H-indole-3- base) ethyl]-hexanamide
[0084] (3S)-N-Desmethylmaprotamol 0.35g (1.60mmol) was slightly heated and dissolved in 10mL of acetonitrile, and triethylamine 0.3mL (2.15mmol) was added. 0.61 g (1.81 mmol) of the compound of Example 2 was added under stirring, refluxed for 4 hours, cooled to room temperature, concentrated to dryness, added 10 mL of saturated sodium carbonate solution, and extracted with 15 mL×4 of chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration to dryness gave 0.78g yellow oil, which was subjected to silica gel column chromatography (8%, 20% EtOH / CHCl 3 ) to obtain a nearly colorless oily substance, a small amount of EA was added, and 0.49 g of a white solid was precipitated, with a yield of 64.5%, mp.82-85°C.
[0085] 1 HNMR (CDCl 3 ): 8.85 (s, 1H, NH, heavy water exchange disappears), 7.55 (d, J = 7.8Hz, 1H, ...
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