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Compound used as hexanokinase inhibitor and application thereof

A compound and pharmaceutical technology, applied in the field of drug research and development, can solve problems such as inflammation, liver fibrosis, and unmet clinical needs, and achieve the effect of improving activity and pharmacokinetic properties

Pending Publication Date: 2021-07-23
GUANGZHOU BOJI MEDICINE SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 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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  • Compound used as hexanokinase inhibitor and application thereof
  • Compound used as hexanokinase inhibitor and application thereof
  • Compound used as hexanokinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 2- (1-methyl-3- (2 - ((S) -2-methyl nitric hetericycloone-1-yl) -6- (trifluoromethyl) pyrimidine-4-yl) -3- Nitrogen and bicyclic ring [3.1.0] hexane-6-yl) acetic acid structure is as follows:

[0053]

[0054] The synthetic roadmap of the compound of this embodiment is attached figure 1 As shown, the specific preparation method of the compound of the present embodiment includes:

[0055] Step 1: 1-methylcyclopropane-1-methylene-2,3-formate

[0056] Effermate (10.01 g, 69.38 mmol), benzyl triethyl ammonium chloride (0.16 g, 0.69 mmol) was added to NaH (2.16 g, 90.2 mmol) DMF (100 mL) solution. Ethyl 2-chloropropionate (10.42 g, 76.32 mmol) was slowly added dropwise, and the reaction was stirred at 40 ° C overnight;

[0057] The reaction solution was poured into ice water (30 mL), and methyl tert-butyl ether (30 mL × 2) was extracted, combined with organic phase, saturated brine (80 mL) wash, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure...

Embodiment 2

[0093] 2- (1-methyl-3- (2 - ((S) -2-methyl nitric hetericycloone-1-yl) -6- (trifluoromethyl) pyrimidine-4-yl) -3- Nitrogen and mixed bicyclic ring [3.1.0] hexane-6-yl-2, 2, 4, 4-d 4 Acetic acid, structural formula is as follows:

[0094]

[0095] The synthetic roadmap of the compound of this embodiment is attached figure 2 As shown, the specific preparation method of the compound of the present embodiment includes:

[0096] Step 1: 3-benzyl-1-methyl-3-nitroza bicyclic ring [3.1.0] hexane-6-methylene-2, 2, 4, 4-D 4

[0097] At 0 ° C, the boronide (2.2.10 g, 73.18 mmol, 47%), dripped, slowly dropped into the example, slowly dropped into the example, dripped, slowly dropped into the examples in a solution of sodium borohydride (2.3 g, 54.89 mmol). 1: 3-benzyl-1-methyl-2,4-dioxane-3-nitrogen-1-methyl-2,4-dioxane-3-nitrogen-1-methyl-2,4-dioxy-3-nitrogen-1-methyl-2,4-dioxane-6-formate (5.0 g, 18.03 mmol) tetrahydrofuran (30 mL) solution, drip, and mixed at room temperature overnight....

Embodiment 3

[0120] 2- (1-ethyl-3- (2 - ((S) -2-methyl nitric hetericycloone-1-yl) -6- (trifluoromethyl) pyrimidine-4-yl) -3- Nitrogen-mixed bicyclic ring [3.1.0] hexane-6-yl) acetic acid, structural formula is as follows:

[0121]

[0122] The specific preparation method of the compound of the present embodiment includes:

[0123] Step 1: 1-ethylcyclopropane-1,2,3-trimethoate

[0124] Epiga group (15.0 g, 104.10 mmol) was added to NaH (6.2 g, 156.50 mmol) DMF (100 mL) solution, and 2-bromobutyrate (20.3 g, 104.10 mmol) was slowly added dropwise. ), 60 ° C agitation reaction overnight. The reaction solution was poured into ice water (300 mL), ethyl acetate (300 ml × 2) extracted, combined with organic phase, saturated brine (100 mL) wash, dried over anhydrous sodium sulfate, filtered, concentrated, and the title compound was pale yellow The oil is 13.0 g of the oil, which is not used directly in the next step without further purification.

[0125] Step 2: 1-ethylcyclopropane-1,2,3-trimethoic...

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Abstract

The invention provides a compound serving as a hexanokinase inhibitor and application of the compound. The compound comprises 2-(1-methyl-3-(2-((S)-2-methyl azetidine-1-yl)-6-(trifluoromethyl) pyrimidine-4-yl)-3-azabicyclo [3.1. 0] hexane-6-yl) acetic acid, 2-(1, 5-dimethyl-3-(2-((S)-2-methyl azetidine-1-yl)-6-(trifluoromethyl) pyrimidine-4-yl)-3-azabicyclo [3.1. 0] hexane-6-yl) acetic acid and the like. The compound has good application in preparation of drugs for treating diseases such as T1D, T2D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes mellitus, gestational diabetes mellitus and the like.

Description

Technical field [0001] The present invention belongs to the technical field of drug development, involves a new compound, which is pharmaceutically acceptable salt, its stereoisomer, and its isotope label, especially a compound that can inhibit hexate kinase, which is pharmaceutically Acceptable salts, their stereoisomers and their isotope labels. Background technique [0002] Hexrozen kinase (KHK) is a basic enzyme involved in fructose in vivo metabolism, and plays a very important role in fructose metabolism, catalytic fructose and ATP reaction transforms into sputum-1-phosphate (F1P). Hexybose kinase has two important subtypes in the human body, respectively, ofhex ketosyl kinase A (KHKA), and hexate kinase C (kHKC). Although KHKA has a broader expression in vivo, KHKC has higher expression in the human body (such as liver, kidney and intestines) (Ishimoto, Lanaspa et al, PNAS 109, 4320-4325, 2012), thus KHKC More remarkable in the regulation of fructose metabolism. [0003] E...

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蔡春满关建通严科池
Owner GUANGZHOU BOJI MEDICINE SERVICES
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