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Preparation method of physostigmine derivatives with resistance to activity of senile dementia disease

A technology for inhibiting activity and substances, applied in the field of synthetic derivatives of physostigmine, which can solve the problems of short action time, narrow therapeutic window, and low bioavailability, and achieve the effect of short synthetic route

Inactive Publication Date: 2011-07-06
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, pharmacists have found that physostigmine has a good curative effect on senile dementia (Greig, N.H. et al. J. Med. Chem. 2005, 48, 986), but the action time is short, the bioavailability is low, and the treatment The narrow window greatly limits its use in the clinic (Al-Jafari, A.; Kamal, M.A.; Greig, N.H.; Alhomida, A.S.; Perry, E.R. Biochem. Biophys. Res. Commun. 1998, 248, 180)

Method used

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  • Preparation method of physostigmine derivatives with resistance to activity of senile dementia disease
  • Preparation method of physostigmine derivatives with resistance to activity of senile dementia disease
  • Preparation method of physostigmine derivatives with resistance to activity of senile dementia disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Synthesis of Implementation Example 1 Compound 6

[0035]

[0036] After trifluoroacetic acid (1.6mL, 21.61mmol) and compound 5 (2.36g, 8.28mmol) were stirred at room temperature for 10 minutes, compound 3 (12.0g, 51.72mmol), 34mL of dichloromethane and 6mL of water were added successively, and the reaction The liquid was cooled to -78°C, and acrolein 4 (35 mL, 0.52 mol) was slowly added. After the completion of the reaction was monitored by TLC, the reaction solution was raised to 0° C., and the reaction was quenched by adding a phosphate buffer solution with pH=7. Extracted with diethyl ether (3×50mL), combined the organic phases, dried with anhydrous sodium sulfate, filtered and sucked dry to obtain an orange-yellow solid, which was subjected to silica gel column chromatography (20% EA / PE) to obtain compound 6 (13.0 g, yield rate 87%). 1 H NMR (400MHz, CDCl 3 )δ1.97(m, 2H), 2.13-2.16(m, 2H), 2.2-2.8(m, 1H), 2.42(m, 1H), 2.89(s, 1H), 2.98(s, 3H), 3.71 (s, 3H), ...

Embodiment 2

[0037] Implementation Example 2 Synthesis of Compound 7

[0038]

[0039] Compound 6 (12.0 g, 41.67 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and lithium aluminum tetrahydride (9.5 g, 0.25 mol) was added in batches under an ice bath, and the reaction solution was heated to reflux. After the completion of the reaction was monitored by TLC, a saturated sodium sulfate aqueous solution was added dropwise to the reaction liquid under an ice bath until the white solid no longer increased, filtered, and the filter residue was washed repeatedly with ethyl acetate, and the organic phases were combined and drained. Recrystallized 3 times with ether, the mother liquor was concentrated and dried by silica gel column chromatography (5-10% MeOH / CH 2 Cl 2 ) to obtain compound 7 (9.8 g, yield 95.%). M.p.71-72℃; 1 H NMR (400MHz, CDCl 3 )δ1.31(m, 1H), 1.47(m, 1H), 1.75(dd, J=12, 4.4Hz, 1H), 1.85(dd, J=12, 4.4Hz, 1H), 1.95(m, 1H ), 2.02(m, 1H), 2.51(s, 3H), 2.53(m, 1H), 2.69(...

Embodiment 3

[0040] Implementation Example 3 Synthesis of Compound 1a

[0041]

[0042] Compound 7 (6.0 g, 24.39 mmol) was dissolved in 100 mL of dry toluene, 60.0 g of Raney nickel was added, and the reaction solution was refluxed for water separation, then heated to reflux for 4 hours. After TLC monitors that the reaction is complete, the Raney nickel is filtered off, the filter residue is washed repeatedly with ethyl acetate, the organic phases are combined, drained, and the crude product is separated and purified by silica gel column chromatography (1-5% MeOH / CH 2 Cl 2 ), to obtain compound 1a (2.68 g, yield 51%). 1 H NMR (400MHz, CDCl 3 )δ0.75(t, J=7.2Hz, 3H), 1.70(sext, J=7.2Hz, 1H), 1.82(sext, J=7.2Hz, 1H), 1.93(m, 1H), 2.01(m, 1H), 2.52(s, 3H), 2.55(m, 1H), 2.68(m, 1H), 2.94(s, 3H), 4.16(s, 1H), 6.41(d, J=7.6Hz, 1H), 6.67(t, J=7.6Hz, 1H), 6.95(d, J=7.6Hz, 1H), 7.08(t, J=7.6Hz, 1H)ppm; 13 C NMR (100MHz, CDCl 3 )δ10.0, 32.5, 36.4, 37.8, 39.3, 52.6, 57.5, 93.8, 106.5, 117.5, ...

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Abstract

The invention belongs to the field of organic synthesis and pharmaceutical chemistry and relates to synthetic derivatives of a natural product, namely physostigmine, as shown in a chemical structural formula 2, which have the activity of inhibiting acetylcholinesterase. In addition, the invention further relates to a preparation method of physostigmine derivatives 2, and the structure of the derivatives is basically characterized by enabling indole 5-bit to have 1,2,3-triazole substituent. The preparation method has the advantages of being short in synthetic routes, and being economic and efficient. The in vitro activity screening study shows that part of the newly synthesized physostigmine derivatives have strong activity of inhibiting the acetylcholinesterase, and are candidate medicaments with potential clinical application prospect for preventing senile dementia disease.

Description

technical field [0001] The present invention relates to a series of synthetic derivatives of the natural product physostigmine with acetylcholinesterase inhibitory activity. In addition, the present invention also relates to a preparation method of a new synthetic derivative of physostigmine and its potential application value in the development of anti-senile dementia drugs. Background technique [0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system that often occurs in the elderly and pre-senile. Behavior, etc., with the development of the disease, the patient will eventually completely lose the ability to live until death. In recent years, with the increase in the average life expectancy of the world's population and the increasing emergence of aging problems, the rate of Alzheimer's disease has shown an upward trend year by year. At present, the number of patients with Alzheimer's disease in the world has reached 24 million, and my cou...

Claims

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Application Information

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IPC IPC(8): A61K31/4192A61K31/454A61K31/5377A61K31/496C07D487/04A61P25/28
Inventor 秦勇王福生宋颢
Owner SICHUAN UNIV
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