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Novel halo-(3-(phenylsulfonyl)prop-1-enyl)pyridine derivative and use thereof

A chlorobenzenesulfonyl and fluorobenzenesulfonyl technology, applied in the field of Nrf2 activators, can solve the problems of low solubility, bioavailability and drug metabolism stability, and achieve the effect of treating or preventing diseases

Pending Publication Date: 2021-06-08
KOREA INST OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, VSC2 has low bioavailability and drug metabolism stability when administered in vivo, low solubility in water, and drug-induced cardiotoxicity, therefore, it is still necessary to find a drug that can overcome these problems

Method used

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  • Novel halo-(3-(phenylsulfonyl)prop-1-enyl)pyridine derivative and use thereof
  • Novel halo-(3-(phenylsulfonyl)prop-1-enyl)pyridine derivative and use thereof
  • Novel halo-(3-(phenylsulfonyl)prop-1-enyl)pyridine derivative and use thereof

Examples

Experimental program
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preparation example Construction

[0067] The preparation method of the present invention may further include reacting with an excess acidic solution to provide the compound represented by Chemical Formula 1 in a salt form after the reaction, but is not limited thereto.

[0068] For example, in the preparation method of the present invention, when R 1 for , used as a reactant ((R 1 -substituted phenyl) sulfonyl) methyl phosphonic acid diethyl ester can be obtained by making (hydroxyl-C 1-5 Alkyl) morpholines react with methanesulfonyl halides to prepare morpholinyl (C 1-5 Alkyl) methanesulfonate the first a-1 step; And make morpholino (C 1–5 Preparation for step a-2 of reaction of alkyl)methanesulfonate with diethyl (hydroxyphenylsulfonyl)methylphosphonate, but not limited thereto. For example, commercially available products can be purchased and used, or products can be used without limitation and / or synthesized using modified methods known in the art.

[0069] Here, the a-1th step can be obtained by add...

preparation example 1

[0097] Preparation Example 1: Synthesis of (hydroxybenzenesulfonyl) methylphosphonic acid diethyl ester

[0098] Step 1-1: Synthesis of methyl (diethoxyphosphoryl)4-methylbenzenesulfonate from diethyl hydroxymethylphosphonate

[0099]

[0100] (diethoxyphosphoryl)methyl4-methylbenzenesulfonate was synthesized according to the above reaction formula. Specifically, diethyl hydroxymethylphosphonate (diethyl hydroxymethylphosphonate, 10 g, 0.06 mol) was dissolved in methylene chloride (MC), and triethylamine ((triethylamine, 9.80 mL, 0.07 mmol) and 4 - Toluenesulfonyl chloride (4-toluenesulfonyl chloride, 13.3g, 0.07mol), stirred at room temperature for 3.5 hours. After the reaction was completed, dilute the reaction solution with ethyl acetate (ethyl acetate; EtOAc), wash with water and brine (brine), and then wash with Anhydrous Na 2 SO 4 The organic layer was dried and filtered. The residue obtained by distillation of the solvent under reduced pressure was purified by ...

Embodiment 1

[0197] Example 1: Synthesis of (E)-3-fluoro-2-(2-(2-fluorobenzenesulfonyl)vinyl)pyridine (compound 1)

[0198]

[0199] After dissolving diethyl (2-fluorobenzenesulfonyl)methylphosphonate (1-3a, 1 eq) prepared according to Preparation 1 in anhydrous THF (0.1 M), the reaction mixture was distilled using dry ice and acetone Cool to -78°C. n-BuLi (1.2eq, 2.0M solution in cyclohexane) was slowly dropped into the solution and stirred for 1 hour, then 3-fluoropicolinaldehyde (3-fluoropicolinaldehyde, 1.2eq) was added and reacted for another hour. If the reaction was confirmed to be incomplete by TLC, the reaction was carried out at room temperature for another 30 minutes. After quenching the reaction with a small amount of water, the reaction mixture was extracted with water and 10% MeOH / MC, washed with anhydrous Na 2 SO 4 A small amount of water was removed from the organic layer, and the solvent was distilled off under reduced pressure and dried in vacuo. Then, the product ...

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Abstract

The present invention relates to a novel halo-(3-(phenylsulfonyl)prop-1-enyl)pyridine derivative or a pharmaceutically acceptable salt thereof, a method for producing same, and an NRF2 activator and a pharmaceutical composition which comprise same as an active ingredient, the pharmaceutical composition being for preventing or treating diseases induced by a reduction in NRF2 activity.

Description

technical field [0001] The present invention relates to a novel halogenated-(3-(phenylsulfonyl)prop-1-ene)pyridine derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, an Nrf2 activator containing it as an active ingredient, and a method for preventing Or a pharmaceutical composition for treating diseases caused by reduced Nrf2 activity. Background technique [0002] Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a cap'n'collar (CNC) family of basic region leucine zippers (Cap'n'Collar family basic region-leuzine zip per), a transcription factor that binds to regional Antioxidant Response Element (ARE) sequences involved in the expression of various genes in the guard cell to induce gene transcription. Although not all antioxidant enzyme expression is induced by ARE-inducing substances, studies using Nrf2-null mice that have artificially knocked out this transcription factor have found that the expression of antioxidant enzy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/44A61K31/496A61K31/5355C07D413/12
CPCA61P1/16A61P25/16A61P25/28A61P25/00A61P17/06A61P25/08A61P25/24A61P25/22A61P11/00A61P13/12C07D213/61C07D239/30C07D401/12A61K31/44A61K31/496A61K31/5355C07D413/12C07D213/52C07F9/4071
Inventor 朴骐德裵爱任林相敏朴钟铉崔智媛金時院金炫姃延瑟基
Owner KOREA INST OF SCI & TECH
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