Tacrine-bifendate hybrid compound, its preparation method and application

A biphenyl diester and hybrid technology, which is applied in the field of tacrine-biphenyl diester hybrid, can solve the problems of poor human body tolerance, poor water solubility, retention and the like

Active Publication Date: 2018-06-19
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the activity and efficacy of these compounds have been significantly improved compared with tacrine, due to factors such as poor water solubility and poor human tolerance, these derivatives only stay in the phase I clinical stage

Method used

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  • Tacrine-bifendate hybrid compound, its preparation method and application
  • Tacrine-bifendate hybrid compound, its preparation method and application
  • Tacrine-bifendate hybrid compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] Methyl-7,7'-dimethoxy-5'-(4-(1,2,3,4-tetrahydroacridin-9-amino)butylcarboxamido)-4,4'-diphenyl [d][1,3]dioxymethylene-5-carboxylate.

[0039] Will N 1 -(1,2,3,4-tetrahydroacridine-9-amino)butyl-1,4-butanediamine (1.0mmol), biphenyl diester acid chloride (1.0mmol), triethylamine (0.5mL ) was dissolved in 20mL of chloroform, stirred at room temperature for 12 hours, after the reaction was completed, the solvent was evaporated to dryness, 30mL of ethyl acetate was added, washed three times with water, and the organic layer was washed with anhydrous Na 2 SO 4 Dry, evaporate the solvent to dryness, and separate by silica gel column chromatography. The eluent is chloroform:methanol:ammonia=200:5:1 (volume ratio).

[0040] The product is light yellow solid, yield: 61%, 1 H NMR (400MHz, CDCl 3 )δ7.90(d, J=9.6Hz, 2H), 7.51(t, J=8.2Hz, 1H), 7.31(t, J=8.2Hz, 1H), 7.17(s, 1H), 7.00(s, 1H), 6.27(t, J=5.9Hz, 1H), 5.94(d, J=1.1Hz, 1H), 5.91(d, J=1.1Hz, 1H), 5.89(dd,...

Embodiment 2

[0042]

[0043] Methyl-7,7'-dimethoxy-5'-(6-(1,2,3,4-tetrahydroacridin-9-amino)hexylcarboxamido)-4,4'-di Phenyl[d][1,3]dioxymethylene-5-carboxylate.

[0044] Method is the same as embodiment one, and difference is to use N 1 -(1,2,3,4-tetrahydroacridin-9-amino)hexyl-1,6-hexanediamine instead of N 1 -(1,2,3,4-tetrahydroacridine-9-amino)butyl-1,4-butanediamine, finally a light yellow solid was obtained.

[0045] Yield: 41%, 1 H NMR (400MHz, CDCl 3 )δ7.99(dd, J=12.4,8.4Hz,2H),7.55(t,J=8.1Hz,1H),7.35(t,J=7.7Hz,1H),7.23(s,1H),7.05( s,1H),6.21(t,J=5.9Hz,1H),5.97(d,J=7.6Hz,2H),5.92(s,2H),4.47(s,1H),3.92(s,3H), 3.90(s,3H),3.76(s,3H),3.51(t,J=6.9Hz,2H),3.32(dd,J=13.5,6.8Hz,1H),3.11-2.99(m,3H),2.70 (s,2H),1.90(s,4H),1.65-1.55(m,2H),1.32-1.17(m,4H),1.13-1.03(m,2H). 13 C NMR (100MHz, CDCl 3 )δ167.95,167.41,157.18,151.57,147.90,146.45,145.93,143.27,142.82,138.48,136.20,130.70,128.93,127.27,124.45,123.85,123.08,119.49,115.13,110.76,110.69,108.31,107.89,102.63,102.08 ,56.74,56.45...

Embodiment 3

[0047]

[0048] Methyl-7,7'-dimethoxy-5'-(8-(1,2,3,4-tetrahydroacridin-9-amino)octylcarboxamido)-4,4'- Diphenyl[d][1,3]dioxymethylene-5-carboxylate.

[0049] Method is the same as embodiment one, and difference is to use N 1 -(1,2,3,4-tetrahydroacridine-9-amino)octyl-1,8-octanediamine instead of N 1 -(1,2,3,4-tetrahydroacridine-9-amino)butyl-1,4-butanediamine, finally a light yellow solid was obtained.

[0050] Yield: 66%, 1 H NMR (400MHz, CDCl 3 )δ7.98(d, J=8.0Hz, 1H), 7.93(d, J=8.4Hz, 1H), 7.55(t, J=7.1Hz, 1H), 7.34(t, J=7.6Hz, 1H) ,7.23(s,1H),7.06(s,1H),6.11(t,J=5.8Hz,1H),5.98(dd,J=8.4,1.1Hz,2H),5.92(s,2H),4.17( s,1H),3.93(d,J=2.0Hz,6H),3.76(s,3H),3.50(t,J=7.2Hz,2H),3.31(dq,J=13.6,6.9Hz,1H), 3.10-2.97(m,3H),2.70(s,2H),1.93-1.90(m,4H),1.69-1.60(m,2H),1.40-1.31(m,2H),1.26-1.14(m,6H ),1.07-0.97(m,2H). 13C NMR (100MHz, CDCl 3 )δ167.87,167.42,157.94,151.11,147.92,146.87,146.42,143.31,142.85,138.51,136.19,130.78,128.54,128.18,124.42,123.69,122.95,119.94,115.54,110.75,...

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Abstract

The invention relates to tacrine-bifendate heterocomplex as well as a preparation method and an application thereof, and belongs to the field of medicine and chemical industry. The heterocomplex has a general structure of the following formula (I) or formula (II) as shown in the specification, wherein R1=H or Cl, R2=H or Cl; Y=CH2, NCH3, NH, carbonyl, oxalyl, 1,3- malonyl, p-cyclohexane or OCH2CH2O; m=0 to 4, n=0 to 4; m and n are respectively of an integer, and a carbon end of -CH2-NH- of the formula (II) is disposed at 3-position or 4-position. The compounds expressed by the structural formula (I) and (II) have an excellent effect of inhibiting acetylcholin esterase. The invention further relates to an application of a medicinal composition of the tacrine-bifendate heterocomplex and a medicinal composition adopting the tacrine-bifendate heterocompolex as an active component in treating, improving or preventing relevant diseases mediated by acetylcholin esterase.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to tacrine-bifendate hybrid compound, its preparation method and application. Background technique [0002] Alzheimer's disease (Alzheimer disease, AD) is a neurodegenerative disease, discovered by the German neuropathologist Alois Alzheimer in 1907, manifested as the degeneration of the central nervous system, neurofibrillary tangles and cellular The pathological features of senile plaques appear outside. Clinically, patients gradually develop memory loss, cognitive dysfunction, behavioral abnormalities, and social barriers, etc., and usually the condition is progressively aggravated until they completely lose the ability to live independently. [0003] Alzheimer's is a very common disease among the elderly, and has become the fourth leading cause of death in the elderly after tumors, heart disease, and cerebrovascular diseases. With the acceleration of th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14A61K31/473A61P25/28
CPCC07D405/14
Inventor 罗稳王超杰洪琛张鑫王婷陈颖赵永梅
Owner HENAN UNIVERSITY
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