A compound for inhibiting acetylcholinesterase activity, and preparation method and uses thereof

A technology of acetylcholinesterase and compounds, which is applied in the field of chemical synthesis of drugs, can solve problems such as failure to market successfully and inability to reverse the course of the disease, and achieve the effect of low production cost, simple process route, and good acetylcholinesterase inhibitory activity

Inactive Publication Date: 2016-01-27
XIAMEN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently a large number of drug studies focused on this area, but none of them have been successfully marketed
[0004] The medicine of Alzheimer's disease listed at present mainly is acetylcholinesterase inhibitor, has tacrine (Davis, K.L.; PowchickP.TheLancet1995,345 (8950), 625-630.), donepezil (BrysonHM; BenfieldP.DrugAging1997, 10(3), 234.), Rivastigmine (Gabelli C. Current Medical Research and 2003,19(2),69-82.), Galantamine (Sramek,JJ; FrackiewiczEJ; CutlerNR.Expertopiniononinvestigationaldrugs2000,9(10),2393-2402.), but they can only relieve symptoms, but cannot reverse course of disease

Method used

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  • A compound for inhibiting acetylcholinesterase activity, and preparation method and uses thereof
  • A compound for inhibiting acetylcholinesterase activity, and preparation method and uses thereof
  • A compound for inhibiting acetylcholinesterase activity, and preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 2. 3-Dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (Ⅰ 1 )

[0039] Add 1.37g (10mmol) anthranilic acid (Ⅲ 1 ), 1.14ml (11mmol) 2-pyrrolidone (Ⅳ 1 ) and 6ml of phosphorus oxychloride, reflux at 100°C for 1 hour under anhydrous conditions, and after natural cooling, pour the reactant into crushed ice, adjust the pH of the system to 8 with potassium bicarbonate, extract three times with 100ml of dichloromethane, reduce The solvent was removed by rotary evaporation. The product was separated by column chromatography using dichloromethane as eluent. Obtain light brown product 1.246g, productive rate 67%, obtained product I 1 The structural formula is as follows:

[0040]

[0041] 2,3-Dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one.

[0042] (CDCl 3 ,500Hz)2.236~2.321(m,2H,CH 2 -CH 2 -CH 2 ),3.140~3.199(m,2H,N=CH 2 -CH 2 -CH 2 ),4.169~4.226(d,2H,CH-CH 2 -N),7.302~7.727(m,3H,Ar-H),8.237~8.280(s,1H,Ar-H).

Embodiment 2

[0044] 6-Chloro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (Ⅰ 2 )

[0045] Add 1.73g (10mmol) 4-chloro-2-aminobenzoic acid (Ⅲ 2 ), 1.14ml (11mmol) 2-pyrrolidone (Ⅳ 1 ) and 6ml of phosphorus oxychloride, reflux at 100°C for 1 hour under anhydrous conditions, and after natural cooling, pour the reactant into crushed ice, adjust the pH of the system to 8 with potassium bicarbonate, extract three times with 100ml of dichloromethane, reduce The solvent was removed by rotary evaporation. DMF / H 2 O mixed solvent recrystallization [69] . 1.652 g of a brown product was obtained, with a yield of 75%. The resulting product I 2 The structural formula is as follows:

[0046]

[0047] 6-Chloro-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one

[0048] (CDCl 3 ,500Hz)2.197~2.258(m,2H,N=CH 2 -CH 2 -CH 2 ),3.088~3.120(t,2H,N=CH 2 -CH 2 -CH 2 ),4.109~4.138(t,2H,CH-CH 2 -N), 7.211~7.306(s, H, Ar-H), 7.543~7.547(s, H, Ar-H), 8.103~8.120(s, 1H, Ar-H).

Embodiment 3

[0050] 7,8,9,10-tetrahydroaza[2,1-b]quinazolin-12(6H)-one (Ⅰ 3 )

[0051] Add 1.37g (10mmol) anthranilic acid (Ⅲ 1 ), 1.695g (15mmol) caprolactam (Ⅳ 2 ) and 6ml of phosphorus oxychloride, reflux at 100°C for 1 hour under anhydrous conditions, and after natural cooling, pour the reactant into crushed ice, adjust the pH of the system to 8 with potassium bicarbonate, extract three times with 100ml of dichloromethane, reduce The solvent was removed by rotary evaporation. The product was separated by column chromatography using dichloromethane as eluent. 1.521 g of a yellow product was obtained with a yield of 71%. The resulting product has structural formula I 3 as follows:

[0052]

[0053] 7,8,9,10-Tetrahydro-6H-azepino[2,1-b]quinazolin-12-one

[0054] (CDCl 3 ,500Hz)1.734~1.824(m,6H,CH 2 -CH 2 -CH 2 ),2.984~3.006(t,2H,N=CH 2 -CH 2 -CH 2 ),4.308~4.325(t,2H,CH-CH 2 -N),7.208~7.373(s,H,Ar-H),7.522~7.538(s,H,Ar-H),7.617~7.935(s,H,Ar-H),8.166~8.184(s,1H ,Ar-H).

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Abstract

The invention discloses a compound for inhibiting acetylcholinesterase activity. The compound is characterized as the structure of the compound is described in the description, wherein n=1-3, R1 is selected from oxyl, halogen, alkyl, -H, -CN or -NO<2>. The compound can be simultaneously bound with a plurality of application sites such as a catalytic site of the AChE center and a peripheral anion site, has good inhibition activity for acetylcholinesterase, and can be used in medicine for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis drugs, and specifically relates to a compound capable of inhibiting the activity of acetylcholinesterase or a preparation method and application thereof. Background technique [0002] Alzheimer's disease (Alzheimer, AD) was first discovered by German Bavarian psychiatrist and neuroanatomist Alois Alzheimer (1864-1915). It is the most common neurodegenerative disease in the elderly. The incidence rate increases with age, usually between 60 and 70. The prevalence rate is about 5% for those over 65 years old, and 20% for those over 85 years old. When people are diagnosed with the disease, they usually live for 5-10 years, and eventually the patient dies within 5-10 years. my country is entering an aging society, and the number of sick people is increasing exponentially. The society has also paid more attention to Alzheimer's disease. Research on drugs that can effectively relieve and tre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P25/28
CPCC07D487/04
Inventor 陈丹林于晨
Owner XIAMEN MEDICAL COLLEGE
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