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Indenone derivative and applications thereof as developing agent and aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle

A compound and complex technology, applied in the field of preparation of labeled compounds, can solve the problems of slow clearance, large trauma and risk of biopsy

Inactive Publication Date: 2011-09-14
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both methods have obvious disadvantages: biopsy has greater trauma and risk, autopsy can only be used for postmortem diagnosis, etc.
18 Deficiency in FDDNP is slower to clear from normal brain regions

Method used

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  • Indenone derivative and applications thereof as developing agent and aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle
  • Indenone derivative and applications thereof as developing agent and aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle
  • Indenone derivative and applications thereof as developing agent and aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Example of labeling method of radioactive isotope

[0058] 1. 11 C mark (shown in the following reaction formula):

[0059]

[0060] In a 3 mL V-shaped flask, 1 mg (0.0036 mmol) of compound 2-(4-dimethylamino-benzylidene)-5-hydroxy-1-indanone was dissolved in 400 μL DMSO, 10 mg dry KOH was added, and vortexed for 5 min. [ 11 C]CH 3 I was bubbled through the solution at 30 mL / min, and the reaction was heated at 95 °C for 5 min. Then, the reaction product was purified by semi-preparative HPLC, Prodigy ODS column, eluent was 70% acetonitrile / 30% triethylamine phosphate buffer (pH7.2), collected containing 11 C labeled radioactive compound.

[0061] 2. 125 I mark (shown in the following reaction formula):

[0062]

[0063] Sequentially weigh the compound 2-(4-dimethylamino-benzylidene)-5-bromo-1-indanone 400mg (1.17mmol), bistributyltin 4.0g (7.02mmol) and tetrakistriphenylphosphine palladium Pd(PPh 3 ) 4 135mg (0.12mmol), add 8mL dioxane and 2mLe...

Embodiment 2

[0070] Embodiment 2: Design example of complexes

[0071] 1. Ligand example:

[0072]

[0073] In the ligand structure shown in the above structural formula (1-4), a multi-dentate coordination site is constructed on the benzene ring. This coordination site can be located at other positions of the benzene ring, and can also be moved to the benzene ring connected to indanone superior. In this multidentate coordination region, single bonds can be replaced by carbon-carbon double bonds or triple bonds, and double bonds can also be reduced to single bonds. The heteroatoms therein can be O, N, S, P.

[0074] Design example of ferromagnetic complex (shown in the following reaction formula)

[0075]

[0076] Taking the above ligand 1 as an example, prepare the Mn complex (as shown in the following reaction formula)

[0077]

[0078] In 20mL of DMF, add bromoethanol 375mg (3mmol), (E)-2-(4-dimethylamino-benzylidene)-5,6-diamino-1-indanone 293mg (1mmol) and carbonic acid P...

Embodiment 3

[0081] A method for synthesizing a series of derivatives using indanone as a raw material, wherein D8a-c, D8e-h, D8l and D8m can be easily obtained by base catalysis, and the operation is simple and the yield is high. D8d can be obtained by reducing D8c under the catalysis of SnCl2 2H2O, and D8h and D8j can be refluxed with (Bu3Sn)2 under the catalysis of Pd(PPh3)4 in triethylamine to obtain tributyltin-substituted products D8i and D8k. D8i reacts with iodine in THF to obtain iodo product D8j. The reaction process is shown in the following reaction formula:

[0082]

[0083] (E)-2-Benzylidene-5,6-dimethoxy-1-indanone (D8a). Weigh 192 mg (1 mmol) of 5,6-dimethoxy-1-indanone and 106 mg (1 mmol) of benzaldehyde in 10 mL of ethanol, add 2.2 mL of 10% NaOH aqueous solution dropwise under stirring, stir overnight at room temperature, and precipitate a large amount of yellow precipitation. After suction filtration, the filter cake was recrystallized from ethanol (yield 86%). ...

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PUM

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Abstract

The invention relates to a compound in a general formula (1), applications of pharmaceutically acceptable salt, esters, amides or predrug of the compound as a developing agent and an aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle, a preparation method of a labeled compound used for development, and a method for conveying the compound to the amyloid protein deposit and the neurofibrillary tangle. When the compound is taken as the developing agent used for detecting in vivo or tissue amyloid protein deposit and neurofibrillary tangle, appropriate radioactive isotope or a contrast agent applicable to magnetic resonance detection needs to be used for labeling the compound. The compound is especially used for the diagnosis and treatment of patients with amyloid protein deposit and neurofibrillary tangle diseases including Alzheimer disease.

Description

field of invention [0001] The present invention relates to a new biologically active compound and its application, a method for diagnosis and treatment using a radioactive isotope or magnetic resonance contrast agent-labeled compound, and a preparation method for the labeled compound. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive aggravation. The main clinical manifestations are cognitive decline, irreversible memory loss, disorientation and language dysfunction. Brain tissue autopsy confirmed a large number of senile plaques (SPs) formed by amyloid-β (Aβ) peptide aggregation and many neurofibrillary tangles (neurofibrillary tangles) formed by filaments of hyperphosphorylated tau protein. NFTs), and the loss of neurons and synapses, etc., the amyloid deposits mentioned in the present invention include but are not limited to senile plaques. [0003] Senile plaques and neurofibrillary tangles compose...

Claims

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Application Information

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IPC IPC(8): C07C49/755C07C45/74C07C205/45C07C201/12C07C225/22C07C221/00C07F7/22A61K31/122A61K31/136A61P25/28A61P35/00A61P3/10A61P9/10A61P9/00A61P21/00A61P25/00A61K51/04A61K49/10A61K101/00A61K101/02A61K103/00A61K103/10
Inventor 周江宁乔金平甘昌胜汪琛玮葛金芳南豆豆
Owner UNIV OF SCI & TECH OF CHINA
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