5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound, preparation method, pharmaceutical composition and application of 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound

A technology of formylglycine and hydroxypyridine, which is applied in the direction of active ingredients of heterocyclic compounds, drug combinations, antipyretics, etc., can solve problems such as poor compliance, limited curative effect, and prone to adverse reactions, and achieves wide application and excellent preparation method Simple and feasible, excellent therapeutic effect

Pending Publication Date: 2022-04-12
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] Purpose of the invention: Aiming at the shortcomings of existing compounds such as limited curative effect, poor compliance, and prone to adverse reactions, the present invention aims to provide a class of highly efficient and low-toxic 5-aliphatic heterocyclic compounds targeting prolyl hydroxylase 2 protein targets Base-3-hydroxypyridine-2-formylglycine compound, preparation method, pharmaceutical composition and application

Method used

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  • 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound, preparation method, pharmaceutical composition and application of 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound
  • 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound, preparation method, pharmaceutical composition and application of 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound
  • 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound, preparation method, pharmaceutical composition and application of 5-fat heterocyclyl-3-hydroxypyridine-2-formyl glycine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: (5-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)-3-benzyloxy-pyridine-2-formyl)glycine methyl ester

[0044] (3-Benzyloxy-5-bromo-3-hydroxypicolinyl)glycine methyl ester (2g, 5.27mmol) was dissolved in 40mL of 1,4-dioxane, and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (1.79g, 5.8mmol), Pd(dppf) 2 Cl 2 (115mg, 0.158mmol), 2M Cs 2 CO 3Solution (5.16g, 15.82mmol) 10mL was heated up to 100°C and reacted under nitrogen atmosphere for 1 hour and 30 minutes. After the reaction was complete, the reaction solution was suction-filtered to remove the palladium catalyst, and the filtrate was sequentially extracted with ethyl acetate (80 mL×3) and washed with saturated sodium chloride solution (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ...

Embodiment 2

[0045] Example 2: (5-(1,2,5,6-tetrahydropyridin-4-yl)-3-benzyloxy-pyridine-2-formyl)glycine methyl ester

[0046] (5-(N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)-3-benzyloxy-pyridine-2-formyl)glycine methyl ester (1.2g, 2.49mmol ) was dissolved in 30 mL of dichloromethane, cooled to 0°C, added trifluoroacetic acid (3.7 mL, 49.84 mmol), and reacted at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete, ice water (10 mL) was added to quench the reaction, the reaction solution was extracted with dichloromethane (30 mL×3), and washed with saturated sodium chloride solution (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was recrystallized using a solvent (petroleum ether: ethyl acetate = 20:1) to obtain the product as an off-white powder (810mg, 85.2%). mp 113.7–114.8°C 1 H NMR (400MHz, DMSO-d6) δ8.79(t, J=6.1Hz, 1H), 8.28(d, J...

Embodiment 3

[0047] Example 3: (6-chloro-5-(1-(4-chlorophenyl)-piperidin-4-yl)-3-hydroxy-pyridine-2-formyl)glycine

[0048] (6-Chloro-5-(1-(4-chlorophenyl)-1,2,5,6-tetrahydropyridin-4-yl)-3-benzyloxy-pyridine-2-formyl)glycine methyl ester

[0049] (6-Chloro-5-(1,2,5,6-tetrahydropyridin-4-yl)-3-benzyloxy-pyridine-2-formyl)glycine methyl ester (100mg, 0.26mmol) was dissolved in 5mL To toluene, add 4-chlorobromobenzene (55mg, 0.28mmol), palladium acetate (2.94mg, 0.013mmol), BINAP (7.97mg, 0.015mmol), cesium carbonate (256mg, 0.78mmol) and react at 100°C for 10 hours. After the reaction was completed, the palladium catalyst was removed by suction filtration, and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2), and the product was obtained as an off-white powder (47mg, 36.4%). mp 182.4–183.7°C. 1 H NMR (400MHz, Chloroform-d) δ8.46 (d, J = 1.4Hz, 1H), 8.31 (t, J = 9.8Hz,...

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Abstract

The invention discloses a 5-fat heterocyclic group-3-hydroxypyridine-2-formyl glycine compound, a preparation method, a pharmaceutical composition and an application of the 5-fat heterocyclic group-3-hydroxypyridine-2-formyl glycine compound. The structure of the compound is as shown in formula (I), and the compound comprises pharmaceutically acceptable salts or a mixture thereof. The compound can improve the amount of HIF-2alpha in cells by inhibiting the activity of prolinyl hydroxylase 2 protein, further promote transcription of EPO genes in the cells, improve the concentration of EPO in plasma and finally promote erythropoiesis of the body, thereby achieving the purpose of treating renal anemia. The prepared medicine can exert efficacy at the molecular level, the cellular level and the animal level, and is wide in application.

Description

technical field [0001] The present invention relates to a class of 5-aliphatic heterocyclyl-3-hydroxypyridine-2-formylglycine compounds, preparation methods, pharmaceutical compositions and applications, in particular to a class of 5-alpha that can effectively inhibit prolyl hydroxylase 2 -Heteroaliphatic-3-hydroxypyridine-2-formylglycine compound, preparation method, pharmaceutical composition and application. Background technique [0002] Chronic kidney disease (chronic kidney disease, CKD) is a type of progressive, irreversible disease in which the patient's GFR is less than 60ml / min / 1.73m 2 Chronic disease with different types of complications as the main feature. Anemia is a serious complication of chronic kidney disease, so anemia induced by chronic kidney disease is also called renal anemia. Renal anemia is caused by insufficient secretion of endogenous erythropoietin (EPO) and functional iron deficiency caused by long-term inflammatory state in patients with chroni...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D409/14A61K31/4545A61K31/4439A61K31/444A61K31/55A61K31/4709A61P7/06A61P13/12A61P19/02A61P29/00A61P37/06A61P1/00A61P35/00A61P9/10
Inventor 张晓进苏凯俊方绍聪李治红张林坚
Owner CHINA PHARM UNIV
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