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Gardenamide A-tacrine diad compound as well as preparation method and application thereof

A technology of gardenia amide and compound, applied in the field of medicinal chemistry, can solve problems such as need for in-depth research, lack of therapeutic drugs, etc., and achieve the effect of delaying degradation

Active Publication Date: 2017-04-19
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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  • Gardenamide A-tacrine diad compound as well as preparation method and application thereof
  • Gardenamide A-tacrine diad compound as well as preparation method and application thereof
  • Gardenamide A-tacrine diad compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Synthesis of 10-N-(2-(10-aminogardeninamide A)amino)ethyltacrine (TNG-1)

[0063] Include the following steps:

[0064] (1) Preparation of intermediate compound G-2: Weigh genipin (340.2mg, 1.5mmol) and imidazole (308.5mg, 4.5mmol) in a 25mL round bottom flask, dissolve with 3mL dry tetrahydrofuran solution; then Dimethyl tert-butyl silicon chloride (TBSCl) (408.8 mg, 2.7 mmol) was weighed, dissolved in dry tetrahydrofuran solution, and added dropwise to the reaction system. The reaction was stirred at room temperature for 1.5 hours. After the reaction was completed, the solvent was directly spin-dried. The residue was separated and purified by liquid column chromatography (petroleum ether: ethyl acetate = 10:1 (V:V)) to obtain 451.2 mg of a white compound with a yield of 89%. The characterization data for the white compound is 1 H NMR (300MHz, CDCl 3 )δ: 7.55 (s, 1H, 3-H), 5.83 (brs, 1H, 1-H), 4.80 (d, J = 12Hz, 1H, CH), 4.31-4.25 (q, J = 12, 18Hz, 2H)...

Embodiment 2

[0074] Example 2: Synthesis of 10-N-(3-(10-aminogardeninamide A) amino) n-propyl tacrine (TNG-2)

[0075] Include the following steps:

[0076] (1) Preparation of intermediate compound DG: prepared according to steps (1) to (4) of Example 1;

[0077] (2) Preparation of intermediate compound T-4: prepared according to steps (5) to (7) of Example 1;

[0078] (3) Preparation of intermediate compound TN-2: prepared according to step (8) of Example 1. Ethylenediamine (8.65mmol) was replaced by 1,3-propanediamine (8.65mmol). 0.25g 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,-NH 2 ), 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 an intermediate compound TN-2;

[0079] (4) Preparation of 10-N-(3-(10-aminogardeninamide A)amino)n-propyltacrine (TNG-2): prepared ...

Embodiment 3

[0081] Example 3: Synthesis of 10-N-(4-(10-aminogardeninamide A) amino) n-butyltacrine (TNG-3)

[0082] Include the following steps:

[0083] (1) Preparation of intermediate compound DG: prepared according to steps (1) to (4) of Example 1;

[0084] (2) Preparation of intermediate compound T-4: prepared according to steps (5) to (7) of Example 1;

[0085] (3) Preparation of intermediate compound TN-3: prepared according to step (8) 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 confirm that this compound is the intermediate compound TN-3.

[0086] (4) Preparation of 10-N-(4-(10-aminogardeninamide A)amino)n-butyltacrine (TNG-3): prepa...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses a gardenamide A-tacrine diad compound as well as a preparation method and application thereof. The structural formula of the compound is shown as formula I. The compound is prepared through the following steps: (1) genipin is adopted as a raw material I and hemiacetal at the C-1 position of genipin is converted into lactone firstly, lactone is converted into lactam secondly, and hydroxyl at the C-10 position is oxidized into aldehyde finally, thereby obtaining an intermediate compound DG; (2) methyl anthranilate is adopted as a raw material II and chloro tacrine is prepared through hydrolysis and cyclization reactions firstly, and an intermediate compound TN-n is prepared through a nucleophilic substitution reaction between chloro tacrine and corresponding diamine secondly; and (3) the target compound is obtained through an amination-reduction reaction between the prepared intermediate compound DG and intermediate compound TN-n. The compound disclosed by the invention is reported for the first time, has a treating effect on neurodegenerative diseases, and can be applied to preparation of a drug for treating the neurodegenerative diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a gardenia amide A-tacrine doublet 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 and PD are the most common and most frequent. The patients of neurodegenerative diseases are mainly the elderly. As the population ages, the incidence rate will i...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/473A61P25/00A61P25/28
CPCC07D401/12
Inventor 陈河如王日康赵家强张磊
Owner JINAN UNIVERSITY
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