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Substituted pyridazinone compound and application thereof

A compound and representative technology applied in the field of medicinal chemistry to achieve strong THβ selectivity and good pharmacokinetic parameters

Active Publication Date: 2021-04-13
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 pyridazinone compound and application thereof
  • Substituted pyridazinone compound and application thereof
  • Substituted pyridazinone compound and application 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-oxy)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] In a 1L round-bottom flask were added 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) , the temperature was raised to 70 °C, silver nitrate (3.4 g, 0.2 mol) was added, and finally an aqueous solution of ammonium persulfate (91.3 g dissolved in 200 mL of water) was added dropwise. The reaction was carried out at 70°C for 30 min. TLC showed that the reaction of the raw materials was complete. The reaction was stopped, and the reaction solution was lowered to room temperature. The pH was adjusted to 9-10 with concentrated ammonia water, extracted with ethyl acetate (200 mL×3), and the organic phases were combined, and the organic phases were satura...

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] A 100 mL round-bottom flask was charged with 4-amino-2-fluorophenol (5.08 g, 40 mmol), acetic anhydride (4.08 g, 40 mmol) and glacial acetic acid (30 mL), and stirred at room temperature overnight. The solid obtained after the solvent was spin-dried was rinsed with ethyl acetate for several times, placed in an oven and dried 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] In a 100 mL round-bottomed flask, compound 2-1 (0.62 g, 3.0 mmol), 2,6-dichloro-4-aminophenol (0.51 g, 3.0 mmol) and potas...

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) urethane (42-1)

[0076] Ethyl carbamate (3.12 g, 20 mmol) and 40 mL of acetonitrile were added to a 100 mL eggplant flask, and after stirring to dissolve, trimethyl orthoformate (3.5 mL, 40 mmol) and acetic anhydride (20 mL) were added. The reaction solution was heated to 80°C and reacted for 4 hours, the reaction was stopped, and 50 mL of ether was added to dry the solvent to obtain a suspension, which was kept in a refrigerator at 2-8°C overnight. The suspension was filtered, and the filter cake was rinsed with ether for several times, placed in an oven and dried 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. Synth...

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Abstract

The invention provides a substituted pyridazinone compound and application thereof. The substituted pyridazinone compound is a compound shown in a general formula I, or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvent compound, a polymorphic form, a stereoisomer or an isotope variant of the substituted pyridazinone compound. The compound disclosed by the invention can be applied to preparation of medicines for preventing and / or treating diseases related to abnormal thyroid hormone functions. The compound has higher THbeta selectivity; the compound has better pharmacokinetic parameters and ideal compound stability; and while the selectivity is improved, the activation activity on THbeta is also obviously 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, and a medicinal preparation and medicinal use thereof. Background technique [0002] In general, thyroid hormone (THyroid hormone, TH) is produced by the thyroid gland and is produced by 3,5,3',5'-tetraiodo-L-thyronine (T4) and 3,5,3'-triiodo Two forms of -L-thyronine (T3) are secreted into the circulatory system, of which T3 plays a major physiological role. [0003] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). TRs belong to a family of nuclear receptors that include two subtypes: TRα and TRβ. TRs are encoded by different genes located on human chromosomes 17 and 3, respectively. Different protein isoforms are generated by selective splicing of primary transcripts. There are many TR isoforms found so far, mainly including TRα1, TRα2, TRα3, TRβ1, TRβ2 and T...

Claims

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Application Information

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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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