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CHR20/21-tacrine heterozygote compound as well as preparation method and application thereof

A CHR20, compound technology, applied in organic chemistry, drug combination, nervous system diseases, etc., can solve problems such as lack of therapeutic drugs and in-depth research.

Active Publication Date: 2017-12-29
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The incidence of senile dementia is increasing year by year. The drugs used to improve AD clinically are mainly anticholinergic and NMDA receptor inhibitors. So far, there is still a lack of ideal therapeutic drugs. Research on the pathogenesis of AD and new The development of therapeutic drugs still needs in-depth research

Method used

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  • CHR20/21-tacrine heterozygote compound as well as preparation method and application thereof
  • CHR20/21-tacrine heterozygote compound as well as preparation method and application thereof
  • CHR20/21-tacrine heterozygote compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1: 10-N-(2-(10-amino CHR20 / 21) amino) ethyl tacrine (TNC-1)

[0087] Synthesis includes the following steps:

[0088] (1) Preparation of anthranilic acid: take methyl anthranilic acid (12.1g, 80mmol) in a 250mL round-bottomed flask, add 50mL of saturated aqueous sodium hydroxide solution, and heat in an oil bath at 105°C for 2.5 after h. After the reaction is completed, cool to room temperature. At this time, the solution is orange-yellow. Use 1.0mol / L dilute hydrochloric acid to adjust the pH value of the system to about 3-4. At this time, a small amount of white solid precipitates out; add glacial acetic acid dropwise to the reaction system, and a large amount of A white solid was precipitated, filtered with suction, the filter cake was washed with water, and dried in vacuo to obtain 10.4 g of a white solid with a yield of 95%. Melting point 144-146°C (literature value: 144-146°C) (Carlier P.R., Han Y.F., Chow E.S. Bioorg. Med. Chem. 1999, 7, 351-357). The ...

Embodiment 2

[0096] Example 2: 10-N-(3-(10-amino CHR20 / 21) amino) n-propyl tacrine (TNC-2)

[0097] Synthesis includes the following steps:

[0098] (1) Preparation of intermediate compound T-4: prepared according to steps (1) to (3) of Example 1;

[0099] (2) Preparation of intermediate compound 1a-dmp: prepared according to steps (5) to (6) of Example 1;

[0100] (3) Preparation of intermediate compound TA-2: prepared according to step (4) of Example 1. Ethylenediamine (8.65mmol) was replaced by 1,3-propanediamine (8.65mmol). 0.25 g of yellow oily liquid was obtained, and the yield was about 85%. 1 H NMR (300MHz, CDCl 3 )δ: 8.16-8.13(d, J=9Hz, 1H), 7.88-7.85(d, J=9Hz, 1H), 7.64-7.59(m, 1H), 7.44-7.38(m, 1H), 4.1(s , 2H, -NH2), 2.66 (t, J = 12Hz, 2H), 2.39 (t, J = 12Hz, 2H), 2.27-2.19 (m, 2H), 1.55-1.42 (m, 4H). The above data confirm that this compound is intermediate compound TA-2;

[0101] (4) Preparation of 10-N-(3-(10-amino CHR20 / 21) amino) n-propyl tacrine (TNC-2): prepared a...

Embodiment 3

[0103] Example 3: 10-N-(4-(10-amino CHR20 / 21) amino) n-butyl tacrine (TNC-3)

[0104] Synthesis includes the following steps:

[0105] (1) Preparation of intermediate compound T-4: prepared according to steps (1) to (3) of Example 1;

[0106] (2) Preparation of intermediate compound 1a-dmp: prepared according to steps (5) to (6) of Example 1;

[0107] (3) Preparation of intermediate compound TA-3: prepared according to step (4) of Example 1. Ethylenediamine (8.65mmol) was replaced by 1,4-butanediamine (8.65mmol). 0.25 g of yellow oily liquid was obtained, and the yield was about 81%. 1 H NMR (300MHz, CDCl 3 )δ:7.94-7.92(d,J=6.0Hz,1H),7.88-7.86(d,J=6.0Hz,1H),7.53-7.49(m,1H),7.32-7.29(m,1H),4.18 (s,1H,-NH-),3.47(t,J=12.0Hz,2H),3.01(m,2H),2.94(m,4H),2.71-2.66(m,4H),1.67-.62( m,2H), 1.54-1.49(m,2H). The above data confirmed that this compound was intermediate compound TA-3.

[0108] (4) Preparation of 10-N-(4-(10-amino CHR20 / 21) amino) n-butyl tacrine (TNC-3): prepared acc...

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Abstract

The invention belongs to the technical field of medicinal chemistry and discloses a CHR20 / 21-tacrine heterozygote compound, a preparation method thereof and an application of the compound in preparation of a drug for treating neurodegenerative diseases. The CHR20 / 21-tacrine heterozygote compound has the structural formula shown in the formula I, wherein n ranges from 1 to 7. The invention also provides the preparation method of the CHR20 / 21-tacrine heterozygote compound. The CHR20 / 21-tacrine heterozygote compound can be used for preparing the drug for treating the neurodegenerative diseases, has a treatment effect on the neurodegenerative diseases and particularly can be used for preparing a drug for treating the Alzheimer's disease, particularly, a drug for treating the Alzheimer's disease caused by injury of dopaminergic neurons. Compared with other prior arts, the compound is simple to prepare and has the curative effect superior to that of tacrine.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a CHR20 / 21-tacrine hybrid compound, a preparation method thereof, and an application in preparation of drugs for treating neurodegenerative diseases. Background technique [0002] Neurodegenerative diseases are a group of diseases that cause brain loss or physical dysfunction by destroying neurons that maintain normal brain function. Clinically, there are mainly Alzheimer's disease (Alzheimer's disease, AD), amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy , multiple sclerosis, Parkinson's disease (Parkinson's disease, PD), primary lateral sclerosis and spinal muscular atrophy, among which AD is the most common and most frequent. [0003] AD is a neurodegenerative disease, clinically manifested as progressive memory and higher cortical function decli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61P25/28
Inventor 陈河如张磊张潮
Owner JINAN UNIVERSITY
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