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Fused ring compound used as hexosylkinase inhibitor

A compound and heterocyclic technology, applied in the field of hexacyclic compounds as hexokinase inhibitors, can solve problems such as inflammation, liver fibrosis, and even liver cancer

Inactive Publication Date: 2020-07-17
GUANGZHOU BOJI MEDICINE SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Metabolism-associated fatty liver disease (MAFLD) has received extensive attention in recent years, with a global incidence of about 25%. Further development will lead to inflammation, and subsequent deterioration may lead to liver fibrosis and even liver cancer. At present, metabolism-associated fatty liver disease has It has become an increasingly common chronic liver disease worldwide and is currently the number one cause of liver transplantation in the United States. Unfortunately, there is currently no drug officially approved for metabolic-related fatty liver disease, and there is a huge unmet clinical need

Method used

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  • Fused ring compound used as hexosylkinase inhibitor
  • Fused ring compound used as hexosylkinase inhibitor
  • Fused ring compound used as hexosylkinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3- The structural formula of azabicyclo[3.1.0]hexan-6-yl)acetic acid is as follows:

[0080]

[0081] The synthetic route diagram of the compound described in this embodiment is as attached figure 1 As shown, the specific preparation method of the compound described in this embodiment includes:

[0082]Step 1: Ethyl 1-methylcyclopropane-1-carboxylate-2,3-methylcarboxylate

[0083] At room temperature, add dimethyl fumarate (10 g, 69.38 mmol) and benzyltriethylammonium chloride (0.16 g, 0.69 mmol) to a solution of NaH (2.16 g, 90.2 mmol) in DMF (100 mL), slowly Ethyl 2-chloropropionate (10.42 g, 76.32 mmol) was added dropwise, and the reaction was stirred overnight at 40°C.

[0084] Pour the reaction solution into ice water (30 mL), extract with methyl tert-butyl ether (30 mL×2), combine the organic phases, wash with saturated brine (80 mL), dry over anhydrous sodium sulfate, filter, an...

Embodiment 2

[0117] 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3- Azabicyclo[3.1.0]hexan-6-yl-2,2,4,4-d 4 ) acetic acid

[0118] The structural formula is as follows:

[0119]

[0120] The synthetic route diagram of the compound described in this embodiment is as attached figure 2 As shown, the specific preparation method of the compound described in this embodiment includes:

[0121] Step 1: 3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester-2,2,4,4-d 4

[0122] At 0°C, slowly drop boron trifluoride diethyl ether (22.10 g, 73.18 mmol, 47%) into a solution of sodium borodeuteride (2.3 g, 54.89 mmol) in tetrahydrofuran (50 mL). Benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (5.0g, 18.03mmol) in tetrahydrofuran (30mL) solution, dropwise , stirred overnight at room temperature. The reaction solution was cooled in an ice bath, and then slowly added dropwise ethanol (50 mL). Part of the so...

Embodiment A

[0144] Embodiment A: in vitro enzymatic activity experiment

[0145] There are two isoforms of ketohexokinase, KHKc and KHKa, among which KHKc has more than ten times the ability to phosphorylate fructose than KHKa.

[0146] According to the metabolic pathway of fructose, the enzyme function of KHK is to consume ATP to convert fructose into fructose-1-phosphate and produce ADP at the same time. The consumption of NADH and the final product NAD can be detected by ATP depletion method, ADP chromogenic method, or by subsequent reactions + The generation of , can effectively measure the inhibition of the reaction.

[0147] The content of NADH was monitored by continuously measuring the absorbance at 340nm, and the inhibition of the candidate compound to KHK was preliminarily judged according to the consumption of NADH. The method involves a coupled enzyme system, and the 3-step reactions involved are as follows:

[0148]

[0149] 3-step reaction involved in initial screening...

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PUM

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Abstract

The invention provides a compound or a pharmaceutically acceptable salt thereof or a stereoisomer or isotope labeled compound thereof. The compound has a good inhibition effect on hexokinase. Meanwhile, the invention also provides a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope labeled compound thereof. The invention further discloses an application of the compound or the pharmaceutically acceptable salt or the stereoisomer or isotope labeled compound in preparation of drugs for treating diseases such as T1D, T2D, LADA, EOD, YOAD, MODY, dystrophy related diabetes and gestational diabetes.

Description

technical field [0001] The present invention relates to a new compound, its pharmaceutically acceptable salt, its stereoisomer and isotope-labeled compound, especially a compound capable of inhibiting ketohexokinase, its pharmaceutically acceptable salt, Its stereoisomers and isotopically labeled compounds. Background technique [0002] Ketokinase (KHK) is a basic enzyme involved in the metabolism of fructose in the body and plays a very important role in fructose metabolism, catalyzing the reaction of fructose and ATP to convert fructose-1-phosphate (F1P). There are two important isoforms of ketohexokinase in the human body, ketohexokinase A (KHKa) and ketohexokinase C (KHKc). Although KHKa is more widely expressed in vivo, KHKc is more highly expressed in major metabolic organs (such as liver, kidney and intestine) in the human body (Ishimoto, Lanaspa et al., PNAS109, 4320-4325, 2012), so KHKc has a greater It is more significant in the regulation of fructose metabolism....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07F9/6558C07D401/14C07F9/6574C07D409/14C07D417/14C07D413/14A61K31/506A61K31/675A61P3/10A61P5/48A61P13/12A61P27/02A61P3/04A61P3/06A61P1/16A61P35/00A61P9/04A61P9/10A61P9/12A61P11/00A61P19/02A61P19/10A61P27/12A61P3/00A61P15/00A61P7/02A61P19/06A61P15/10A61P17/00A61P1/00A61P25/28A61P25/18A61P1/04
CPCC07D403/14C07F9/65583C07D401/14C07F9/657181C07D409/14C07D417/14C07D413/14A61P3/10A61P5/48A61P13/12A61P27/02A61P3/04A61P3/06A61P1/16A61P35/00A61P9/04A61P9/10A61P9/12A61P11/00A61P19/02A61P19/10A61P27/12A61P3/00A61P15/00A61P7/02A61P19/06A61P15/10A61P17/00A61P1/00A61P25/28A61P25/18A61P1/04
Inventor 王建华王廷春唐昌华邓检阳许小飞
Owner GUANGZHOU BOJI MEDICINE SERVICES
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