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9-position substituted pyrido[3,4-b]indole derivatives, preparation method thereof and use as sirt protein inhibitor

A technology of substituents and compounds, applied in the field of SIRT protein inhibitors, can solve the problems of no reports of SIRT5 inhibitor drugs

Active Publication Date: 2018-01-19
XIHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there are currently no reports of better SIRT5 inhibitors

Method used

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  • 9-position substituted pyrido[3,4-b]indole derivatives, preparation method thereof and use as sirt protein inhibitor
  • 9-position substituted pyrido[3,4-b]indole derivatives, preparation method thereof and use as sirt protein inhibitor
  • 9-position substituted pyrido[3,4-b]indole derivatives, preparation method thereof and use as sirt protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] The preparation of embodiment 1 compound key intermediate of the present invention

[0108] 1. Synthesis of compound 2-(9H-pyrido[3,4-b]indol-9-yl)ethyl acetate (3)

[0109]

[0110] Put the raw material compound 1 (0.50g, 2.98mmol) and NaH (0.24g, 5.96mmol) purchased from Bailingwei CAS No. 244-63-3; Product No. 230515 into a round bottom flask, and then dissolve it with 10mL DMF , after stirring at room temperature for 2 h, compound 2 (0.49 mL, 4.46 mmol) was added dropwise to the above reaction solution, and reacted at room temperature for 5 h, and TLC detected that the reaction of the raw materials was basically complete.

[0111] Add water, extract 3 times with ethyl acetate, the organic layer is dried over magnesium sulfate, after concentrating, the crude product is subjected to silica gel column chromatography (CH 2 Cl 2 :CH 3 OH=60: 1) purification to obtain light yellow solid compound 3 (0.40 g, yield 54%).

[0112] Compound 3: 1 H NMR (400MHz, DMSO-d6)...

Embodiment 2

[0128] The solvent was distilled off under reduced pressure, and saturated NaHCO 3 The pH was adjusted to 8, extracted three times with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated to obtain light yellow solid compound 9 (0.12 g, yield 86%). Synthesis of Example 2 Compound N-benzyl-2-(9H-pyrido[3,4-b]indol-9-yl)acetamide (5a)

[0129]

[0130] First use 2mLCH 2 Cl 2 Compound 4 (0.05g, 0.22mmol) was dissolved, and benzylamine (0.05mL, 0.44mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt was gradually added under stirring at 0°C salt (EDCI, 0.05g, 0.27mmol), 1-hydroxybenzotriazole (HOBT, 0.04g, 0.27mmol) and N, N-diisopropylethylamine (DIEA, 0.09mL, 0.44mmol), After the addition was completed, the temperature was raised to room temperature and the reaction was stirred for 12 hours. TLC detection showed that the reaction was complete.

[0131] Water was added, extracted three times with dichloromethane, the organic layer w...

Embodiment 3

[0133] Synthesis of Example 3 Compound N-(pyridine-3-methylene)-2-(9H-pyrido[3,4-b]indol-9-yl)acetamide (5b)

[0134]

[0135] First use 2mLCH 2 Cl 2 Dissolve compound 4 (0.03g, 0.13mmol), and gradually add pyridine-3-methylamine (0.03g, 0.26mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon under stirring at 0°C Diimine hydrochloride (EDCI, 0.03g, 0.16mmol), 1-hydroxybenzotriazole (HOBT, 0.02g, 0.16mmol) and N, N-diisopropylethylamine (DIEA, 0.06mL, 0.26mmol), the addition was completed, the temperature was raised to room temperature, and the reaction was stirred for 12h, and TLC detected that the reaction was complete.

[0136] Water was added, extracted three times with dichloromethane, the organic layer was dried over magnesium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (CH 2 Cl 2 :CH 3 OH=10:1) was purified to obtain white solid compound 5b (0.03 g, yield 71%).

[0137] Compound 5b: purity: HPLC test is 98%; 1 H N...

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Abstract

The invention discloses a 9-substituted pyridino-[3,4-b]indole derivative and further discloses a preparation method of the compound and application of the derivative as an SIRT protein inhibitor. The compound can be used for treating various diseases such as tumors, the neurodegenerative disease, the metabolic disease and the like.

Description

technical field [0001] The present invention relates to a 9-position substituted pyrido[3,4-b]indole derivative, and also relates to its preparation method and use as a SIRT protein inhibitor. Background technique [0002] Protein post-translational modification is one of the important means of protein function regulation. Among them, lysine residues are the main sites of a series of post-translational modification processes. The more common post-translational modification forms include acylation, including acetylation, succinyl These acylation modifications are all directly regulated by the Sirtuin (SIRT) family of proteins. Sirtuin (Silent information regulator 2 family, SIRT) is a nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylase and a single ADP-ribosyltransferase, expressed in various tissues and organs , such as liver, heart, brain and pancreas. Based on the similarity of amino acid sequences, SIRT proteins in mammals are divided into seven...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P3/00A61P35/00A61P25/28
CPCC07D471/04
Inventor 杨羚羚王周玉钱珊何彦颖陈泉龙
Owner XIHUA UNIV