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Deuterated MGL-3196 compound and application thereof

A technology for compounds and uses, applied in the directions of active ingredients of heterocyclic compounds, metabolic diseases, drug combinations, etc., can solve problems such as deteriorating pharmacokinetic properties, and achieve good pharmacokinetic properties, treatment of dyslipidemia, and low clearance rate. Effect

Active Publication Date: 2019-12-31
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

), deteriorating its pharmacokinetic properties; on the other hand, the hydrogen at certain positions on the drug molecule is not easy to be deuterated due to steric hindrance and other reasons. unpredictable

Method used

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  • Deuterated MGL-3196 compound and application thereof
  • Deuterated MGL-3196 compound and application thereof
  • Deuterated MGL-3196 compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1. Synthesis of 2-(3,5-dichloro-4-((5-(1,1,1,3,3,3-hexadeuteriopropan-2-yl)-6-oxo-1, 6-dihydropyridazin-3-yl)oxy)benzene)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (1)

[0040]

[0041] 2-trideuteromethyl-3,3,3-trideuteropropionic acid A was prepared by literature method (Canadian Journal of Chemistry, 2014, 92, 305).

[0042]

[0043] Measure 350mL of ethanol into a 500mL three-necked round bottom flask, and stir at room temperature. Subsequently, Na flakes (9.9 g, 430.79 mmol) were slowly added in batches to the system, and when the system was completely clear, the system was transferred to an oil bath to continue heating and stirring. When the internal temperature of the system rose to 70°C, diethyl malonate (30 g, 187.30 mmol) was added dropwise to the system, and after the dropping was completed, the mixture was kept stirring for 15 minutes. Deuteromethyl iodide (57 g, 393.33 mmol) was added dropwise to the system, and the rate of a...

Embodiment 2

[0056] Example 2. Synthesis of 2-(3,5-dichloro-4-((5-(heptadeuterioisopropylpropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)) Phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (2)

[0057]

[0058] Synthesis of 2,3,3,3-tetradeutero-2-(trideuteromethyl)propionic acid (compound B):

[0059]Weigh 2,2-bis(trideuteromethyl)malonic acid (3g, 34mmol) into a 100mL single-neck round bottom flask, add heavy water (15mL) to it, and place the system in a water bath at 60°C The solvent was removed by rotary evaporation, and the operation was repeated twice. Transfer the above substrate into a 35 mL sealed tube, add heavy water (9 mL), seal and place in an oil bath at 160° C., and stir the reaction overnight. After 12 hours, the heating was stopped, and the system was allowed to cool to room temperature, and the solvent was removed at low temperature to obtain compound B (2.1 g) as a colorless transparent oily liquid. It was directly used in the next reaction without furth...

Embodiment 3

[0066] Example 3. Synthesis of 2-(3,5-dichloro-4-((5-(1,1,1-trideuteroprop-2-yl)-6-oxo-1,6-dihydropyridazine -3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (3)

[0067]

[0068] Synthesis of 2-(trideuteromethyl)propionic acid (Compound C)

[0069]

[0070] (1) Synthesis of compound diethyl-2-deuteromethyl-2-methylmalonate

[0071] Measure 350mL of ethanol into a 500mL three-necked round bottom flask, and stir at room temperature. Subsequently, Na flakes (9.9 g, 430.79 mmol) were slowly added in batches to the system, and when the system was completely clear, the system was transferred to an oil bath to continue heating and stirring. When the internal temperature of the system rose to 70°C, 2-methyl-diethyl malonate (20.0 g, 114.80 mmol) was added dropwise to the system, and after the dropping was completed, the mixture was kept stirring for 15 minutes. Deuteromethyl iodide (18.5 g, 196.6 mmol) was added dropwise to the system, and the rat...

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Abstract

The present invention discloses a compound represented by formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate thereof. In the formula (I), R1-R10 are respectively and independently selected from H, D, and are not all H. Compared with a non-deuterated control compound MGL3196, the compound or the optical isomer, the pharmaceutically acceptable salt, the prodrug, the hydrate or the solvate of the compound provided by the invention have the advantages that the agonistic activity on thyroid hormone receptor beta (THR-beta) is better; half-life period is longer, clearance rate is higher, metabolic stability and pharmacokinetic properties are better, and the application prospect in preparation method of THR-beta agonists, and medicines used for treating THR-beta agonist adaptation diseases including dyslipidemia, hypercholesterolemia, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) is promising.

Description

technical field [0001] The present invention relates to deuterated MGL-3196 compound and its use. Background technique [0002] MGL-3196 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 against dyslipidemia, hypercholesterolemia, and nonalcoholic steatohepatitis (NASH). [0003] Deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Since the shape and volume of deuterium in drug molecules are close to hydrogen, deuterated drugs generally retain the biological activity and selectivity of the original drug. Since the C-D bond is more stable than the C-H bond, the C-D bond is less likely to be broken during the chemical reaction of the deuterated drug, and its half-life may be extended. [0004] However, due to the complex metabolic process of biological systems, the pharmacokin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/53A61P3/06A61P1/16
CPCC07D403/12A61P3/06A61P1/16A61K31/53A61P5/16C07B2200/05
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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