Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

BET (bromodomain and extraterminal domain)/HDAC (histone deacetylase) double-target inhibitor, and preparation method and application thereof

An inhibitor and dual-target technology, applied in the field of medicine and chemical industry, can solve the problems of no BI-2536 derivative inhibitor report, etc., and achieve the effects of high yield, simple preparation method and improved therapeutic effect.

Active Publication Date: 2017-08-11
SOUTHEAST UNIV
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are no reports of BI-2536 derivative inhibitors with BET / HDAC dual targets

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • BET (bromodomain and extraterminal domain)/HDAC (histone deacetylase) double-target inhibitor, and preparation method and application thereof
  • BET (bromodomain and extraterminal domain)/HDAC (histone deacetylase) double-target inhibitor, and preparation method and application thereof
  • BET (bromodomain and extraterminal domain)/HDAC (histone deacetylase) double-target inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Take the synthesis of 15c (BI-C) as an example below to further illustrate the present invention:

[0047] 1. Preparation of compound 2, the reaction formula is as follows:

[0048]

[0049] Compound 1 (1g, 9.96mmol) was weighed and dissolved in 10mL of methanol, and thionyl chloride (1.48ml, 20.36mmol) was slowly added in an ice-water bath at 0°C, refluxed at 65°C for 1.5h, and distilled under reduced pressure after the reaction. The remaining oil was mixed with 10ml of methyl tert-butyl ether and stirred for 0.5h. The resulting colorless crystals were filtered, washed with ether, and dried in vacuo overnight to obtain colorless semi-solid crystals, namely the target compound 2 (1.12g, quant.).

[0050] The target product compound 2 1 The data of H NMR are as follows:

[0051] 1H NMR (300MHz, CDCl 3 ) δ: 8.71 (s, 2H), 4.20-4.01 (m, 1H), 3.66 (s, 3H), 2.24-2.02 (m, 2H), 1.09 (t, J=7.0Hz, 3H).

[0052] 2. Preparation of compound 4, the reaction formula is as follo...

example 5-1

[0071] Weigh compound 7 (280mg, 1mmol) and dissolve it in 5ml N,N-dimethylformamide solution, add iodomethane (80μl, 1.3mmol), cool the reaction to -10°C, add 60% Sodium hydride (52mg, 1.3mmol) was reacted at 0°C for 30min, raised to room temperature and reacted for 3h, the plate was spotted to confirm the completion of the reaction, and crushed ice was added to terminate the reaction. Extracted twice with ethyl acetate, washed with water, dried the organic phase with anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and column chromatography gave light yellow compound 8 (294mg, quant.)

[0072] The target product compound 8 1 The data of H NMR are as follows:

[0073] 1 H NMR (300MHz, CDCl 3 )δ:

[0074] 7.67 (s, 1H), 4.38-4.30 (m, 1H), 4.24 (dd, J=7.47Hz, 3.6Hz, 1H), 3.33 (s, 3H), 2.08-2.02 (m, 1H).

example 5-2

[0076] Weigh compound 7 (280 mg, 1 mmol) and dissolve it in 5 ml of tetrahydrofuran solution, add iodomethane (80 μl, 1.3 mmol), cool the reaction to -10 ° C, add 60% sodium hydride (52 mg, 1.3 mmol) dispersed in mineral oil React at 0°C for 30 min, rise to room temperature for 3 h, spot the plate to confirm the end of the reaction, and add crushed ice to terminate the reaction. Extracted twice with ethyl acetate, washed with water, dried the organic phase with anhydrous magnesium sulfate, filtered, distilled under reduced pressure, column chromatography gave light yellow compound 8 (235 mg, yield 80%)

[0077] 6. The synthesis of compound 9, the reaction formula is as follows:

[0078]

[0079] Weigh compound 8 (235mg, 0.8mmol) and 4-amino-3-methoxybenzoic acid (208mg, 1.24mmol) into a mixed solvent of 0.6ml ethanol, 2.4ml water, 260μl concentrated hydrochloric acid, and reflux the reaction mixture at 95°C for 48h . Distillation under reduced pressure and column chromato...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a BET (bromodomain and extraterminal domain) / HDAC (histone deacetylase) double-target inhibitor, and a preparation method and application thereof. The structure of the double-target inhibitor is as shown in the specification, wherein n=2-6. Compared with the prior art, the double-target inhibitor has the advantage that pharmacophore of a BET inhibitor BI-2536 and pharmacophore of an HDAC inhibitor are spliced by a Linker to obtain a novel BET / HDAC inhibitor with BET / HDAC double-target inhibition effect. The preparation method is simple, mild in condition and easy to implement.

Description

technical field [0001] The invention discloses a BET / HDAC dual-target inhibitor, a preparation method and application thereof, and belongs to the technical field of medicine and chemical industry. Background technique [0002] An important feature of many human diseases, especially tumors and autoimmune inflammation, is abnormal acetylation levels that lead to transcriptional abnormalities. The acetylation level of histone lysine is mainly controlled by histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomain proteins (BRDs). [0003] BRD is a kind of protein domain that can specifically recognize histone acetylated lysine (Acetylated lysine, KAc). The 61 BRDs found in the human body exist in 46 proteins, which are divided into 8 families according to their functions, among which bromodomain and extraterminal domain (BET) belong to the second BRD family classes, including BRD2, BRD3, BRD4, and BRDT. BET proteins regulate the expression of target gen...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04
Inventor 蔡进李丛丛吉民徐华刘文景
Owner SOUTHEAST UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com