Deuterated hexanokinase inhibitor and application thereof

A deuterium substitution, compound technology, applied in the field of deuterated hexokinase inhibitors and their uses, can solve the problems of unmet clinical needs, endanger the lives of patients, etc., and achieve good pharmacokinetic properties, good safety, High bioavailability effect

Active Publication Date: 2021-12-07
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, infusions containing fructose, sorbitol, or invert sugar can be life-threatening
This condition has a high unmet clinical need

Method used

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  • Deuterated hexanokinase inhibitor and application thereof
  • Deuterated hexanokinase inhibitor and application thereof
  • Deuterated hexanokinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7- Preparation of Dihydro-5H-cyclopenta[d]pyrimidin-4-yl-6,6-dideuterium)-3-azabicyclo[3.1.0]hexyl-6-yl)acetic acid (compound 1)

[0219] (1) Preparation of 1-ethyl 2,4-dimethyl 1-oxobutane-1,2,4-tricarboxylate

[0220]

[0221] Dissolve sodium ethoxide (6.1g, 90.0mmol) in THF (150mL), add diethyl oxalate (13.1g, 90.0mmol) until the solution is clear, then add dimethyl glutarate (14.4g, 90.0mmol), After the addition was complete, the reaction was carried out at 15°C for 18.5h. Concentrate the solvent, dilute with water, extract with methyl tert-butyl ether, adjust the pH of the aqueous phase to 1 with concentrated hydrochloric acid, extract with ethyl acetate, dry and concentrate the organic phase to obtain 8.9 g of the target compound, wash the methyl tert-butyl ether phase with hydrochloric acid, The organic phase was dried and concentrated to obtain 10 g of the target compound, and a total o...

Embodiment 2

[0254] Example 2 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7- Preparation of dihydro-5H-cyclopenta[d]pyrimidin-4-yl-5-deuterium)-3-azabicyclo[3.1.0]hexyl-6-yl)acetic acid (compound 1a)

[0255] (1) Preparation of dimethyl glutarate-3-deuterium

[0256]

[0257] Add dimethyl glutaconate (6.08g, 38.5mmol) to 50mL of methanol, add 15mL of tetrahydrofuran, nickel chloride (2.4g, 18.5mmol), cool to 0°C, add sodium borodeuteride (2.2 g, 52 mmol), continue to stir for 0.5 h, filter with celite, concentrate, and purify on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain 5.9 g of the target compound, yield: 95.2%.

[0258] (2) Preparation of 1-ethyl 2,4-dimethyl 1-oxobutane-1,2,4-tricarboxylate-3-deuterium

[0259]

[0260] Dissolve sodium ethoxide (2.3g, 33.8mmol) in THF (50mL), add diethyl oxalate (4.9g, 33.5mmol) until the solution is clear, then add dimethyl glutarate-3-deuterium (5.4g, 33.5mmol), after the addition was completed, th...

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PUM

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Abstract

The invention relates to the technical field of medicines, and in particular, relates to a deuterated hexanokinase inhibitor compound, pharmaceutically acceptable salt, ester or stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, a preparation containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, and an application of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof in preparation of drugs for treating and/or preventing KHK-mediated diseases and related diseases.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to a deuterated ketohexokinase inhibitor compound, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, comprising the compound, a pharmaceutically acceptable salt thereof, The pharmaceutical composition and preparation of its ester or its stereoisomer, the preparation method of said compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, and said compound, its pharmaceutically acceptable Use of the salt, its ester or its stereoisomer in the preparation of medicines for treating and / or preventing diseases mediated by KHK and related diseases. Background technique [0002] NAFLD / NASH is the hepatic manifestation of metabolic syndrome. Changes in diet and lifestyle have led to the prevalence of obesity and metabolic syndrome in Western countries and many Asian countries, resulting in a significant increase in the inci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D401/14C07D409/14C07D413/14A61K31/517A61P35/00A61P1/16A61P3/00A61P13/00A61P29/00A61P9/00A61P1/04A61P37/02A61P25/00
CPCC07D403/14C07D401/14C07D409/14C07D413/14A61P35/00A61P1/16A61P3/00A61P13/00A61P29/00A61P9/00A61P1/04A61P37/02A61P25/00C07B2200/05
Inventor 刘斌
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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