Pyridazinone derivative and application thereof

A kind of derivative, the technology of pyridazinone, applied in the field of pyridazinone derivatives and preparation thereof, can solve the problems such as the limitation of therapeutic use, and achieve the effect of good activity

Active Publication Date: 2020-11-10
SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is why the cardiotoxicity of naturally occurring thyroid hormones limits their therapeutic use

Method used

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  • Pyridazinone derivative and application thereof
  • Pyridazinone derivative and application thereof
  • Pyridazinone derivative and application thereof

Examples

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preparation example Construction

[0063] The present invention has no special requirements for the preparation method of the aforementioned pyridazinone derivatives, and those skilled in the art can select a suitable preparation process based on the common knowledge of synthesis based on the target product.

[0064] The present invention also provides an application of the pyridazinone derivatives described in the present invention in the preparation of agonists that stimulate thyroid hormone beta receptors; the pyridazinone compounds of formula (I) provided by the present invention show good Thyroid hormone β receptor agonist has good liver selectivity and can be used as a drug related to the treatment and / or prevention of diseases related to the action.

[0065] Definition of each term:

[0066] It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. In addition, although any methods, devices and materials simila...

Embodiment 1

[0075] 3-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)-3- Malonate

[0076]

[0077] Step 1: Preparation of 3,6-Dichloro-4-isopropylpyridazine (Compound 2)

[0078] Dissolve 3,6-dichloropyridazine (45g, 0.304mol), isobutyric acid (33.45g, 0.380mol), silver nitrate (5.138g, 0.0304mol), trifluoroacetic acid (6.932g, 0.0608mol) in water (270mL) was stirred at 70°C, and ammonium persulfate dissolved in water (180mL) was slowly dropped into the bottle. The reaction solution was stirred for 20 minutes, the heating was stopped, and the temperature was cooled to room temperature. with NaHCO 3 Adjust the pH value of the aqueous solution to 9-10. Extract with n-hexane, combine the organic phases to dry over anhydrous sodium sulfate, filter, remove the solvent under reduced pressure to obtain a residue, and then separate by column chromatography [ethyl acetate / petroleum ether=1 / 3] to obtain 3,6-dichloro-4 - Isopropylpyridazine (56 g, 96% yield)....

Embodiment 2

[0093] (E)-4-((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino )-4-oxo-2-butenoic acid

[0094]

[0095] Step 1: Preparation of (E)-4-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)-4- Oxo-2-butenoic acid methyl ester (compound 6)

[0096] 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (100mg, 0.301mmol), triethylamine (60mg, 0.602mmol) into dichloro Methane (3mL), ice bath, then slowly drop methyl 3-chlorocarbonylacrylate (49mg, 0.331mmol) into the bottle, react at room temperature for 20 minutes, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, Dry over anhydrous sodium sulfate, filter, and remove solvent under reduced pressure to obtain (E)-4-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy )phenyl)amino)-4-oxo-2-butenoic acid methyl ester (140 mg, 104% yield).

[0097] LC-MS (m / z): 444.5 (M+1).

[0098] Step 2: Preparation of (E)-4-((3,5-dichloro...

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Abstract

The invention provides a pyridazinone derivative and an application thereof, the pyridazinone derivative with the structure shown in the formula (I) provided by the invention has good activity as a thyroid hormone beta receptor agonist by selecting a specific modification group. The compound can be used for treating and/or preventing diseases caused by thyroid hormone regulation.

Description

[0001] This application claims the priority of the Chinese patent application submitted to the China Patent Office on May 10, 2019, with the application number 201910391465.7 and the title of the invention "a pyridazinone derivative and its application", the entire content of which is incorporated by reference In this application. technical field [0002] The invention relates to the field of medicinal chemistry, in particular to a pyridazinone derivative and a preparation method and application thereof. Background technique [0003] Thyroid hormone (TH) plays a key role in normal growth and development and maintenance of metabolic balance (Paul MYen, Physiological Reviews, Vol. 81(3): pp. 1097-1126 (2001)). TH can promote the hydrolysis of lipids, increase the utilization of fatty acids, thereby providing energy for the body, and finally lead to the reduction of lipids and weight loss. Studies have shown that the TH level of obese patients has a great change compared with ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D237/16C07D237/32C07D471/04C07D401/14C07D237/22C07D413/12C07F9/6509C07D487/04A61P3/04A61P3/06A61P3/00A61P9/10A61P5/14A61P3/10A61P9/00A61P1/16A61P35/00
CPCC07D403/12C07D237/16C07D237/32C07D471/04C07D401/14C07D237/22C07D413/12C07D487/04A61P3/04A61P3/06A61P3/00A61P9/10A61P5/14A61P3/10A61P9/00A61P1/16A61P35/00C07F9/6509A61K31/501A61P5/16C07D237/14C07D237/34C07D405/12C07D403/14
Inventor 王伟邓舟周游李志斌鲁先平
Owner SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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