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Substituted pyridazinones and uses thereof

The technology of a compound, pyridazinone, is applied in the field of medicinal chemistry to achieve the effects of increased selectivity, enhanced agonistic activity, and good pharmacokinetic parameters

Active Publication Date: 2022-03-01
SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although MGL-3196 as a TRβ agonist can effectively treat a variety of diseases, it is still necessary to find a new class of compounds with better selectivity, low toxicity, beneficial to thyroid hormones, good oral bioavailability and druggability. has great challenges

Method used

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  • Substituted pyridazinones and uses thereof
  • Substituted pyridazinones and uses thereof
  • Substituted pyridazinones and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0045] Synthesis of 2-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-oxyl)phenyl)-3,5-dioxo -2,3,4,5-Tetrahydro-1,2,4-triazine-6-carbonitrile (1)

[0046]

[0047] 1. Synthesis of 3,6-dichloro-4-tert-butylpyridazine (1-1)

[0048] Add 3,6-dichloropyridazine (14.9 g, 0.1 mol), pivalic acid (20.4 g, 0.2 mol), purified water (300 mL) and trifluoroacetic acid (7.4 mL, 0.1 mol) into a 1 L round bottom flask , the temperature was raised to 70° C., silver nitrate (3.4 g, 0.2 mol) was added, and finally ammonium persulfate aqueous solution (91.3 g dissolved in 200 mL of water) was added dropwise. Reacted at 70°C for 30 minutes, TLC showed that the raw materials were completely reacted, stopped the reaction, cooled the reaction solution to room temperature, adjusted the pH to 9-10 with concentrated ammonia water, extracted with ethyl acetate (200mL×3), combined the organic phases, and used saturated Wash with sodium chloride and dry with anhydrous sodium sulfate. Conce...

experiment example 2

[0059] Synthesis of 2-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3-fluorophenyl)-3,5-di Oxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (2)

[0060]

[0061] 1. Synthesis of N-(3-fluoro-4-hydroxyphenyl)acetamide (2-1)

[0062] Add 4-amino-2-fluorophenol (5.08 g, 40 mmol), acetic anhydride (4.08 g, 40 mmol) and glacial acetic acid (30 mL) into a 100 mL round bottom flask, and stir overnight at room temperature. The solid obtained after the solvent was spin-dried was washed with ethyl acetate several times, and placed in an oven at 50°C for 4 h to obtain the target product 2-1 as a brown solid (6.1 g, 90%). LRMS:C 8 h 9 FNO 2 (M+H) + m / z = 170.1, molecular weight = 169.1554, exact mass = 169.0539.

[0063] 2. Synthesis of N-(4-((5-(tert-butyl)-6-chloropyridin-3-yl)oxy)-3-fluorophenyl)acetamide (2-2)

[0064] Add compound 2-1 (0.62g, 3.0mmol), 2,6-dichloro-4-aminophenol (0.51g, 3.0mmol) and potassium carbonate (0.83g, 6.0mmol) in 100mL round bottom fl...

experiment example 3

[0073] Synthesis of 1-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-2,4- Dioxy-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (42)

[0074]

[0075] 1. Synthesis of (2-cyano-3-methoxyacryloyl) ethyl carbamate (42-1)

[0076] Add urethane (3.12g, 20mmol) and 40mL acetonitrile in 100mL eggplant-shaped flask, after stirring to dissolve, add trimethyl orthoformate (3.5mL, 40mmol) and acetic anhydride (20mL). The reaction solution was heated to 80°C for 4 hours, and the reaction was stopped. After the solvent was spin-dried, 50 mL of diethyl ether was added to obtain a suspension, which was left to stand overnight in a refrigerator at 2-8°C. The suspension was filtered, the filter cake was rinsed with diethyl ether several times, and placed in an oven at 50°C for 4 h to obtain the target product 42-1 as a white solid (2.2 g, 56%). LRMS:C 8 h 11 N 2 o 4 (M+H) + m / z = 199.1, molecular weight = 198.1780, exact mass = 198.0641.

[0077] 2. Synthesi...

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Abstract

The present invention provides a substituted pyridazinone compound and its use. The substituted pyridazinone compound is represented by the general formula I, or its pharmaceutically acceptable salt, prodrug, hydrate or solvate, poly Crystalline forms, stereoisomers or isotopic variants. The compound of the present invention can be applied to the preparation of medicines for preventing and / or treating diseases related to thyroid hormone dysfunction. The compound has stronger THβ selectivity; better pharmacokinetic parameters and ideal compound stability; while the selectivity is improved, the agonistic activity on THβ is also significantly enhanced.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, in particular to a pyridazinone compound, a preparation method thereof, a pharmaceutical preparation thereof and a medical application thereof. Background technique [0002] Generally speaking, thyroid hormone (Thyroid hormone, TH) is produced by the thyroid gland and is 3,5,3',5'-tetraiodo-L-thyronine (T4) and 3,5,3'-triiodo -L-thyronine (T3) is secreted into the circulatory system in two forms, of which T3 plays the main physiological role. [0003] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). TRs belong to the nuclear receptor family and include two subtypes: TRα and TRβ. TRs are encoded by different genes located on human chromosome 17 and 3, and different protein isoforms are produced by alternative splicing of primary transcripts. There are many TR isoforms discovered so far, mainly including TRα1, TRα2, TRα3, TRβ1, TRβ2 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12A61K31/53A61K31/506A61K31/501A61P1/16A61P9/10A61P3/04A61P9/12A61P3/06A61P3/10A61P9/00A61P35/00A61P5/14
CPCC07D403/12A61P1/16A61P9/10A61P3/04A61P9/12A61P3/06A61P3/10A61P9/00A61P35/00A61P5/14A61K31/501A61K31/513A61K31/53C07D401/12
Inventor 姚庆强解维林维罗尼克·克伦斯基刘波李妍智英李莹牟艳玲孙敬勇汪海洋吴忠玉陈海蛟丁天地王悦孙皓熠张飞鹏孟鹏刘庆旭李华杰王一戈温山山
Owner SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
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