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Pyridine formylaryl (heteroaryl) alpha-substituted amino acid compound as well as preparation method and application thereof

A compound and heteroaryl technology, applied in the fields of amino acid compounds substituted at the α-position of picolyl aryl (heteroaryl), its preparation and application, which can solve the problem of insufficient activity and selectivity, and few researches on inhibitors, etc. problems, to achieve the effects of treating and preventing anemia, preventing and alleviating gastrointestinal toxicity and hematopoietic function damage, and promoting expression

Active Publication Date: 2020-08-07
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Inhibitor research for FIH is limited and mainly focused on competitive inhibitors of α-ketoglutarate, which are deficient in activity and selectivity

Method used

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  • Pyridine formylaryl (heteroaryl) alpha-substituted amino acid compound as well as preparation method and application thereof
  • Pyridine formylaryl (heteroaryl) alpha-substituted amino acid compound as well as preparation method and application thereof
  • Pyridine formylaryl (heteroaryl) alpha-substituted amino acid compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] Methyl(6-bromopicolinoyl)phenylalaninate (Compound I-1): Add 20ml of anhydrous N,N-dimethyl phenyl formamide, followed by adding EDCI (2.81g, 14.7mmol, 1.5eq), HOBT (2.0g, 14.8mmol, 1.5eq), and then adding phenylalanine methyl ester hydrochloride (3.2g, 14.8mmol, 1.5eq) Finally, TEA (7.0g, 69mmol, 7.0eq) was added and reacted overnight (TLC detection end point). After the reaction, add water and stir, extract with ethyl acetate three times, wash with dilute hydrochloric acid three times, wash with saturated sodium bicarbonate solution three times, dry the organic phase with anhydrous sodium sulfate, and spin off ethyl acetate under reduced pressure to obtain a crude product. The crude product was purified by a flash silica gel column (eluent: petroleum ether: ethyl acetate = 10: 1 ~ petroleum ether: ethyl acetate = 1: 1) to obtain 2.9 g of a light yellow solid with a yield of 81%; 1H NMR (300MHz, DMSO) 68.89 (d, J=8.2Hz, 1H, -NH-), 8.75 (dd, J=2.2, 0.8 Hz, ...

Embodiment 2

[0042]

[0043] Methyl (5-bromopicolinoyl) phenylalaninate (compound I-2): under stirring at room temperature, 50 ml of anhydrous dichloromethane was added to 5-bromo-2-pyridinecarboxylic acid (2.81 g, 13.9 mmol, 1.5 eq), and then Add EDCI (2.67g, 13.9mmol, 1.5eq), HOBT (1.88g, 13.9mmol, 1.5eq) successively, then add phenylalanine methyl ester hydrochloride (2.0g, 9.28mmol, 1.0eq) and finally add TEA (6.7g, 65mmol, 7.0eq), reacted overnight (TLC detection end point). After the reaction, add water and stir, extract with ethyl acetate, wash with dilute hydrochloric acid and saturated sodium bicarbonate solution, dry the organic phase with anhydrous sodium sulfate, and spin off ethyl acetate under reduced pressure to obtain a crude product. The crude product was purified by a flash silica gel column (eluent: petroleum ether: ethyl acetate = 10: 1 ~ petroleum ether: ethyl acetate = 1: 1) to obtain 2.28 g of a light yellow solid with a yield of 68%; 1 H NMR (300MHz, DMSO) δ8.99...

Embodiment 3

[0045]

[0046] Methyl(5-bromopicolinoyl)tyrosinate (compound I-3):, under stirring at room temperature, 50ml of anhydrous dichloromethane was added to 5-bromo-2-pyridinecarboxylic acid (500mg, 2.48mmol, 1.0eq), followed by Add EDCI (721mg, 3.71mmol, 1.5eq), HOBT (502mg, 3.71mmol, 1.5eq), then add tyrosine methyl ester hydrochloride (860mg, 3.71mmol, 1.5eq) and finally add DIPEA (1.92g, 14.9mmol, 6.0eq), reacted overnight (TLC detection end point). After the reaction, add water and stir, extract with ethyl acetate, wash with dilute hydrochloric acid and saturated sodium bicarbonate solution, dry the organic phase with anhydrous sodium sulfate, and spin off ethyl acetate under reduced pressure to obtain a crude product. The crude product was purified by a flash silica gel column (eluent: petroleum ether: ethyl acetate = 10: 1 ~ petroleum ether: ethyl acetate = 1: 1) to obtain 293 mg of a light yellow solid with a yield of 32%; 1 H NMR (300 MHz, DMSO) 69.23 (s, 1H, -PhOH), 8...

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Abstract

The invention relates to the field of medicinal chemistry. The invention relates to the field of organic chemistry, in particular to a pyridine formylaryl (heteroaryl) alpha-substituted amino acid compound I. The compound has the advantages that the activity of asparaginyl hydroxylase is selectively inhibited, so that the transcription activity of hypoxia inducible factors (Hypoxia-inducible factors, HIF) in cells can be promoted, the expression quantity of the hypoxia inducible factors in the cells can be increased, and the expression of downstream genes, such as comprises expression of genessuch as erythropoietin (EPO), a vascular endothelial growth factor (VEGF) and the like, for promoting regulation and control of the hypoxia inducible factor can be enhanced. The invention also relates to a preparation method of the compound and a pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof. The invention also relates to application of the compound or the pharmaceutically acceptable salt thereof in preparation of a medicine for inhibiting asparaginyl hydroxylase or a medicine for treating anemia and ischemic diseases and having a radiation protection effect.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of amino acid compounds substituted at the α-position of picolidyl aryl (heteroaryl), which can selectively inhibit the activity of asparaginyl hydroxylase, and can increase intracellular The transcriptional activity of hypoxia-inducible factor (HIF), which promotes the expression of downstream genes regulated by hypoxia-inducible factor, including erythropotin (EPO), vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and other genes , can be applied to the treatment of anemia, the prevention of anemia and other related diseases, and the radiation protection effect played by enhancing the transcriptional activity of hypoxia-inducible factor. Background technique [0002] With the continuous development of nuclear energy utilization and the wide application of radiotherapy and isotope technology, the probability of nuclear and radiation acciden...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4439A61P7/06A61P1/00A61P39/00
CPCC07D401/04A61P7/06A61P1/00A61P39/00
Inventor 徐文清唐海康李德冠吴静孟鑫成明慧孟媛媛
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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