Isatin histone deacetylase inhibitors as well as preparation method and applications thereof

A histone and inhibitor technology, applied in anti-inflammatory agents, organic chemistry, antiviral agents, etc., can solve the problems of histone deacetylase inhibitor enzyme inhibitory activity and cell tumor inhibitory activity, etc.

Inactive Publication Date: 2014-07-23
WEIFANG BOCHUANG INT ACAD OF BIOTECH & MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The enzyme inhibitory activity and cell tumor inhibitory activity of the existing histone deacetylase inhibitors are not ideal

Method used

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  • Isatin histone deacetylase inhibitors as well as preparation method and applications thereof
  • Isatin histone deacetylase inhibitors as well as preparation method and applications thereof
  • Isatin histone deacetylase inhibitors as well as preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1. Synthesis of compound 8a of the present invention

[0094] (1) 5-Bromoisatin 3

[0095] Add 40mL of water to a three-necked bottle equipped with an electric stirrer, a thermometer and a constant pressure dropper, add anhydrous sodium sulfate (90g) when warming, start the electric stirrer to make it even, add 20ml of chloral hydrate (0.06mol ) aqueous solution, and then slowly drop the solution prepared by p-bromoaniline (1) (0.04mol), concentrated hydrochloric acid (10mL) and water (70mL), with the dropping of p-bromoaniline, a large number of flocculent precipitates will be produced. An aqueous solution (40 mL) of hydroxylamine hydrochloride (0.13 mol) was then added dropwise. After the dropwise addition, the temperature was raised to 85°C, and the reaction progress was monitored by TLC, and the reaction was stopped after 1.5-2.5 hours. The reaction system was rapidly cooled to room temperature, filtered with suction, and dried in the air to obtain the c...

Embodiment 2

[0105] Example 2. Synthesis of compound 8b of the present invention

[0106] The preparation method is the same as that of compound 8a, except that methyl glycine in the reaction reagent is replaced by methyl 4-aminobutyrate. 1H NMR (600 MHz, DMSO) δ 10.36 (s, 1H), 8.70 (s, 1H), 8.27 (t, J = 5.5 Hz, 1H), 7.60 (dd, J = 6.8, 2.0 Hz, 2H), 6.90 – 6.87 (m, 1H), 4.33 (dd, J = 4.1, 2.7 Hz, 2H), 4.32 – 4.30 (m, 2H), 4.25 (s, 2H), 3.05 (dd, J = 12.9, 6.7 Hz, 2H ), 1.96 (t, J = 7.5 Hz, 2H), 1.66 – 1.60 (m, 2H).

Embodiment 3

[0107] Example 3. Compounds of the invention 8c Synthesis

[0108] The preparation method is the same as that of compound 8a, except that the glycine methyl ester in the reaction reagent is replaced by 6-aminocaproic acid methyl ester. 1 H NMR (600 MHz, DMSO) δ 10.34 (s, 1H), 8.67 (s, 1H), 8.23 ​​(t, J = 5.5 Hz, 1H), 7.62 – 7.58 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 4.34 – 4.32 (m, 2H), 4.32 – 4.30 (m, 2H), 4.24 (s, 2H), 3.05 (dd, J = 12.7, 6.7 Hz, 2H), 1.94 (t, J = 7.4 Hz, 2H), 1.51 – 1.44 (m, 2H), 1.40 (dt, J = 14.6, 7.1 Hz, 2H), 1.27 – 1.20 (m, 2H).

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Abstract

The invention relates to isatin histone deacetylase inhibitors as well as a preparation method and applications thereof. The series of compounds have a structure as shown in the general formula I in the specification. Activity screening experiments shows that the histone deacetylase inhibitors have excellent in-vitro and in-vivo activity and can be used for preparing medicines for treating diseases with abnormal expression of histone deacetylase activity. The invention also relates to a medicine composition containing the compounds with a structure as shown in the formula I, as well as an application of the composition in medicine preparation.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a derivative isatin-like histone deacetylase inhibitor and its preparation method and application. Background technique [0002] Histone deacetylases (HDACs) are zinc-dependent or NDA + Dependent enzymes, histone deacetylases (HDACs) can hydrolyze the acetyl group on the terminal amino group of lysine residues of various protein substrates (such as reaction formula II), such as histones, etc., resulting in histones The increase of positive charge density in turn leads to the enhancement of the affinity between histone and negatively charged DNA, and the inhibition of gene transcription. Recently, more and more non-histone proteins have been confirmed as substrates of HDACs, such as transcription factors, cytoskeletal proteins, molecular chaperones, etc. It is precisely because HDACs have such complex functions that their expr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/113A61K31/407A61P35/00A61P25/00A61P31/12A61P29/00A61P35/02A61P33/06A61P3/10
CPCC07D491/113Y02A50/30
Inventor 徐文方金康张颖杰王学建黄永学侯金宁
Owner WEIFANG BOCHUANG INT ACAD OF BIOTECH & MEDICINE
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