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Aldoxime-containing tacrine derivatives selective butyrylcholinesterase inhibitors, preparation method and application thereof

A technology of butyrylcholinesterase and derivatives, which is applied in the field of tacrine derivatives selective butyrylcholinesterase inhibitors and its preparation, can solve the problems of liver toxicity and side effects, withdrawal, etc., and achieve high application value effect

Active Publication Date: 2021-09-24
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Tacrine is the earliest anti-AD drug approved by the FDA. It has high inhibitory activity on acetylcholinesterase and butyrylcholinesterase in vitro, but it has been withdrawn from clinical practice due to its severe liver toxicity.

Method used

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  • Aldoxime-containing tacrine derivatives selective butyrylcholinesterase inhibitors, preparation method and application thereof
  • Aldoxime-containing tacrine derivatives selective butyrylcholinesterase inhibitors, preparation method and application thereof
  • Aldoxime-containing tacrine derivatives selective butyrylcholinesterase inhibitors, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: Preparation of some key intermediates

[0051] Preparation of anthranilic acid (2)

[0052]

[0053] The starting material Isatin 1 (3.00g, 20.4mmol) was added to a 100mL eggplant-shaped flask containing 1M NaOH (40.8mL, 40.8mmol), and H was slowly added dropwise under ice-bath conditions. 2 o 2 (4.4mL, 40.8mmol), after the dropwise addition was completed, the temperature was raised to 30-40°C and stirred for 3h; after the reaction was detected by TLC, the heating was stopped, cooled to room temperature, and the pH was adjusted to 3-4 with 1M HCl solution; subsequently, ethyl acetate Extraction, combined organic layers, washed with saturated brine, combined organic layers, dried over anhydrous sodium sulfate; filtered, evaporated to dryness under reduced pressure; silica gel column chromatography to obtain the pure product (2) of intermediate anthranilic acid, white solid, 2.50 g, 83% yield. mp: 143-145°C. ESI-MS:m / z 138.2(M+1) + ,C 7 h 7 NO 2 (...

Embodiment 2

[0084] Embodiment 2: General method for the preparation of target compounds A1Q4, A2Q17, A2Q19, A2Q20 and A3Q19

[0085] Add intermediates 12, 13, 14 (1.0eq), corresponding aldehyde substituents 15, 16, 17 (1.2eq), and HAc (1.2eq) to 10mL of absolute ethanol in sequence, and reflux at 80°C for 10-12h . The reaction was complete as detected by TLC, the solvent was evaporated to dryness under reduced pressure, and separated by silica gel column chromatography to obtain the target compounds A1Q4, A2Q17, A2Q19, A2Q20, and A3Q19.

[0086]

[0087] White solid, 25 mg, 81% yield, mp: 206-210°C. ESI-MS:m / z 489.1(M+1) + ,C 27 h 25 FN 4 o 4 (488.2). 1 H NMR (400MHz, DMSO-d 6 )δ8.60(s,1H,ONCH),8.43(d,J=8.8Hz,1H,PhH),8.41–8.36(m,1H,PhH),8.25(s,1H,chromene-2-C H ),7.80(s,2H,PhH),7.74(s,1H,PhH),7.72(s,1H,PhH),7.65(s,1H,CONH),7.54(dd,J=14.5,7.0Hz,2H ,PhH),4.54(s,2H,COCH 2 O), 4.01(s, 2H), 3.08(q, J=7.3Hz, 2H), 2.91(s, 2H), 2.63(s, 2H), 1.20(q, J=9.6, 7.3Hz, 4H). 13 CNMR (100MH...

Embodiment 3

[0096] Embodiment 3: Acetylcholinesterase and butyrylcholinesterase enzyme activity test experiment of target compound

[0097] Experimental Materials:

[0098] Test compound, acetylcholinesterase (Type VI-S, from electric eel, C3389; lyophilized powder, from human AChE recombinant, C1682) and butyrylcholinesterase (EC 3.1.1.8, fromequine serum, C7512; lyophilized powder, from human serum, B4186) (both purchased from Sigma company), EP tubes of different specifications (0.5mL, 1.5mL, 10mL, 50mL), micro-samplers of different specifications (10μL, 20μL, 100μL, 200μL, 1000μL), multi-channel pipettes, microtiter plate shakers, Microplate reader, NaCl, MgCl 2 ·6H 2 O, triple distilled water, positive controls tacrine and donepezil.

[0099] Test Methods:

[0100] The test method for the inhibitory activity of acetylcholinesterase and butyrylcholinesterase is the Ellman method.

[0101] (1) Test method for inhibitory activity of acetylcholinesterase (derived from electric eel...

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Abstract

The invention relates to tacrine derivatives containing aldoxime selective butyrylcholinesterase inhibitors, a preparation method and application thereof. The compound has the structure shown in formula I or II. The present invention also relates to pharmaceutical compositions containing compounds of formula I and formula II. The present invention also provides the application of the above compounds and compositions containing one or more of these compounds in the preparation of anti-Alzheimer's disease drugs.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and in particular relates to a selective butyrylcholinesterase inhibitor containing aldoxime-containing tacrine derivatives and a preparation method and application thereof. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease clinically manifested mainly in memory loss, cognitive dysfunction, social impairment and loss of self-care ability. Currently, the pathogenesis of Alzheimer's disease is unclear, and its two main pathological features are extracellular amyloid deposition in the brain and intracellular neurofibrillary tangles. Researchers have proposed a variety of hypotheses on the pathogenesis of AD, such as the cholinergic hypothesis, the β-amyloid protein deposition hypothesis, the oxidative stress theory, and the inflammatory immune theory. At present, only seven drugs for the treatment of AD have been approve...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12C07D401/12A61K31/473A61P25/28
CPCA61P25/28C07D401/12C07D405/12
Inventor 刘新泳荆兰兰展鹏康东伟魏文秀
Owner SHANDONG UNIV
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