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Halogen-substituted phenyl ether compound and application thereof

A technology for compounds and uses, applied in the field of drug preparation, can solve the problems of deteriorating pharmacokinetic properties, inability to prolong half-life, unpredictable sites, etc., and achieve improved pharmacokinetic properties, agonistic activity and agonistic selectivity, Good agonistic effect

Active Publication Date: 2021-02-26
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deuterium at certain sites not only cannot prolong the half-life, but may shorten it (Scott L.Harbeson, Roger D.Tung.Deuterium in Drug Discovery and Development, P405-406), deteriorating its pharmacokinetic properties; another On the one hand, the hydrogen at certain positions on the drug molecule is not easy to be deuterated due to steric hindrance and other reasons. Therefore, the deuterated position of the drug is not arbitrary, and the deuterated position is also unpredictable.

Method used

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  • Halogen-substituted phenyl ether compound and application thereof
  • Halogen-substituted phenyl ether compound and application thereof
  • Halogen-substituted phenyl ether compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The synthesis of embodiment 1, compound 2

[0047]

[0048](1) Synthesis of compound 3-bromo-5-chloro-4-((6-chloro-5-bis(trideuteromethyl)methylpyridazin-3-yl)oxy)aniline (compound 2-1)

[0049]

[0050] Synthesis of 3,6-dichloro-4-(1,1,1,3,3,3-hexadeuteriopropan-2-yl)pyridazine (Compound A):

[0051]

[0052] 2-trideuteromethyl-3,3,3-trideuteropropanoic acid A-4 was prepared by literature method (Canadian Journal of Chemistry, 2014, 92, 305). Weigh 2-trideuteromethyl-3,3,3-trideuteropropionic acid (1.4g, 15mmol) into a 100mL three-neck round bottom flask, add 20mL water to it, stir at room temperature to dissolve and clarify. Then 3,6-dichloropyridazine (2.2 g, 15 mmol) was added to the system and stirred at room temperature. Then silver nitrate (2.5 g, 15 mmol) was added to the system, and the system was transferred to an oil bath to raise the temperature, heat and stir the reaction. When the temperature in the system rose to 50°C, concentrated sulfuric ac...

Embodiment 2

[0063] Example 2, 2-(3-bromo-5-chloro-4-((4-deuterium-5-(1,1,1,3,3,3-hexadeuteriopropan-2-yl)-6- Oxy-1,6-dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6 - Synthesis of Cyanide (Compound 3)

[0064]

[0065] (1) Compound 3-bromo-5-chloro-4-((6-chloro-5-(prop-2-yl-1,1,1,3,3,3-hexadeuterio)pyrazin-3-yl Synthesis of -4-deuterium)oxy)aniline

[0066]

[0067] Synthesis of 3,6-dichloro-4-deuterium-5-(1,1,1,3,3,3-hexadeuteriopropan-2-yl)pyridazine (compound B):

[0068]

[0069]Weigh the compound 2,3-dichloromaleic anhydride B-1 (8.35g, 50mmol), add it to a 100ml round bottom flask, add 40ml water, add hydrazine hydrate (2.5g, 50mmol), heat to reflux, and keep it warm for 4h , cooled to room temperature, ice-water bath for 30min, filtered, the filter cake was rinsed with 100ml of water, and dried to obtain 5.0g of 4,5-dichloromaleic hydrazide (B-2), yield: 55.3%, MS (ESI )m / e 181.0(M+H) + .

[0070] Synthesis of 4,5-dideuterium-maleic hydr...

Embodiment 3

[0084] Example 3, 2-(3,5-dibromo-4-((6-oxo-5-(prop-2-yl-1,1,1,3,3,3-hexadeuterio)-1,6 -dihydropyrazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-cyano (compound 14 )Synthesis

[0085]

[0086] (1) 3,5-dibromo-4-((6-chloro-5-(prop-2-yl-1,1,1,3,3,3-hexadeuterio)pyridazin-3-yl)oxy ) Synthesis of aniline:

[0087]

[0088] Compound 3,6-dichloro-4-(propan-2 base-1,1,1,3,3,3-hexadeuterio)pyridazine A (330mg, 1.67mmol) was dissolved in 5ml DMSO, and compound 4- Amino-2,6-dibromophenol (559mg, 2.09mmol), K2CO3 (923mg, 6.68mmol) was added under stirring, Ar was replaced 3 times, heated to 90°C, reacted for 3h, cooled, added water, extracted with ethyl acetate, The organic layer was washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, separated and purified by column chromatography (petroleum ether / ethyl acetate=5:1) to obtain compound 3,5-dibromo-4- ((6-Chloro-5-(propan-2-yl-...

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Abstract

The invention discloses a halogen-substituted phenyl ether compound and an application thereof. Specifically provided are a compound represented by formula (I) or an optical isomer, a pharmaceuticallyacceptable salt, a prodrug, a hydrate or a non-aqueous solvate thereof. The experiments prove that compared with a control compound MGL-3196, the compound shown in the formula (I), which is obtainedthrough a specific substitution position and a specific substitution type, has better agonistic activity on THR-beta, and the selectivity on THR-beta / THR-alpha is remarkably improved. In addition, thecompound provided by the invention also has significantly improved pharmacokinetic properties. The compound provided by the invention has excellent application prospects in preparation of THR-beta agonists and medicines for treating indications (including dyslipidemia, hypercholesterolemia, non-alcoholic steatohepatitis and non-alcoholic fatty liver diseases) suitable for the THR-beta agonists.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a halogen-substituted phenyl ether compound and its application. Background technique [0002] MGL-3196 is a chlorine atom-substituted phenyl ether compound, which is a highly selective thyroid hormone receptor β (THR-β) agonist, with an EC50 value of 0.21 μM, and its structural formula is Late-stage clinical trials are currently underway, showing efficacy in the treatment of dyslipidemia, hypercholesterolemia, and nonalcoholic steatohepatitis (NASH). [0003] Studies have found that MGL-3196, as a thyroid hormone receptor β agonist, needs to be improved in its pharmacokinetic properties and agonistic activity in vivo. Therefore, the structural modification of MGL-3196 and the development of drugs with better performance have become one of the research hotspots. [0004] However, chemical modification changes the structure of the compound to varying degrees, lea...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D253/075A61P3/06A61P1/16A61P5/14A61K31/53
CPCC07D403/12C07D253/075A61P3/06A61P1/16A61P5/14A61P3/04A61P3/10A61P5/16A61P9/10A61K31/53C07B2200/05
Inventor 杜武李宇李海波陈元伟张承智李兴海
Owner HINOVA PHARM INC
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