Selective butylcholinesterase inhibitor and application thereof
A butyrylcholinesterase, selective technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, nervous system diseases, etc., can solve problems such as cognitive function decline
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[0026] The preparation of embodiment 1 formula 2 compound
[0027]
[0028] Dissolve 4-bromomethylbenzoic acid (200mg, 0.93mmol, 1 equivalent) in 8ml of tetrahydrofuran, add the tetrahydroisoquinoline compound (1.86mmol, 2 equivalents) shown in Formula 1, heat to reflux for 8 hours, and concentrate The reaction solution. The resulting residue was added to 20 mL of sodium hydroxide solution, extracted with dichloromethane (3×20 mL), and the aqueous phase was acidified to pH ~1 with 10% dilute hydrochloric acid to obtain a solid compound of formula 2.
[0029] Table 1 Formula 2 Compound Concrete Structural Formula, Raw Materials Used
[0030]
[0031] Compound of formula 2-1, yellow solid, yield 90%. 1 H NMR (600MHz, DMSO-d 6 )δ11.54(brs,1H,COOH),8.02(d,J=8.2Hz,2H),7.82(d,J=8.2Hz,2H),7.28-7.15(m,4H),4.53(d,J =8.5Hz, 2H), 4.29(d, J=18.0Hz, 2H), 3.63(s, 2H), 3.03(s, 2H). 13 C NMR (150MHz, DMSO-d 6 )δ166.9,134.5,131.8,131.7,131.5,129.7,128.6,128.3,127.7,126.7,126.6,57.8...
Embodiment 2
[0035] The preparation of embodiment 2 general formula I compound
[0036]
[0037] The compound of formula 2 (0.374mmol, 1 equivalent) was dissolved in 5mL of N,N-dimethylformamide, and O-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (156.4mg, 0.411mmol, 1.1eq), the corresponding amine compound (0.374mmol, 1eq) and N,N-diisopropylethylamine (193.3mg, 1.496mmol, 4eq) . The reaction solution was stirred at room temperature overnight, 10 mL of water was added, and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a residue, which was separated and purified by silica gel chromatography to obtain the corresponding compound of general formula I. The compound numbers, specific structural formulas and raw materials are shown in Table 2 below.
[0038] Table 2 general formula I compound specific structural formula, raw materials used
[0039]
[0040] ...
Embodiment 3
[0053] The inhibitory activity of embodiment 3 compound to BChE, AChE enzyme
[0054] Butyrylcholinesterase (BChE), acetylcholinesterase (AChE), thiobutyrylcholine iodide (BUC) and thioacetylcholine iodide (ATC) as substrates, 5,5 - Dithiobis(2-nitrobenzoic acid) (DTNB) was purchased from Sigma. The determination of AChE inhibitory activity was carried out with reference to the method reported by Ellan et al. Add 40 μL of phosphate buffer solution (pH=8.0) to each well of the 96-well plate, and then add 10 μL of 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50 and 100 μM of the test compound solution or blank control into the corresponding air , followed by adding 10 μL of BChE or AChE and incubating on a shaker at 37°C for 5 min. Add 20 μL of DTNB solution and incubate on a shaker at 37°C for 5 minutes, then add 10 μL of substrate BUC or ATC and incubate on a shaker at 37°C for 3 minutes, measure the absorbance at 412 nm with a microplate reader, and calculate the effect of the ...
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