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Six-membered ring formamide compounds, synthesis method and applications thereof

A technology for cyclic formamides and compounds, which is applied in the field of six-membered cyclic formamide compounds and their synthesis, and can solve problems that need further research

Inactive Publication Date: 2020-03-31
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, TDO plays a certain role in the immune escape of various tumors, and the role and mechanism of IDO2 in the tolerance of T cells to tumor immune antigens remain to be further studied

Method used

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  • Six-membered ring formamide compounds, synthesis method and applications thereof
  • Six-membered ring formamide compounds, synthesis method and applications thereof
  • Six-membered ring formamide compounds, synthesis method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0110] Example 1-1, Preparation of the compound N-(3,4-methylenedioxyphenyl)-2(-(4-(hydroxycarbamoyl)benzyl)oxy)benzamide (QZ001)

[0111]

[0112] Dissolve salicylic acid (180mg, 1.3mmol, 1eq) and N,N'-carbonyldiimidazole (CDI, 211mg, 1.3mmol, 1eq) in DMF (5ml), react at 40°C for 30min, and then add 1,8 - Diazabicycloundec-7-ene (DBU, 396mg, 2.6mmol, 2eq) and tert-butanol (193mg, 2.6mmol, 2eq) were reacted at 60°C for 12h. After the reaction, the solvent was removed under reduced pressure, extracted with ethyl acetate and water, and passed through a silica gel column after conventional treatment to obtain the intermediate tert-butyl benzoate (214rrmg, 1.1mmol).

[0113] The intermediate tert-butyl benzoate (214mg, 1.1mmol, 1.0eq) was dissolved in anhydrous acetonitrile (50ml), and methyl 4-bromomethylbenzoate (298mg, 1.3mmol, 1.2eq) and Cs 2 CO 3 (912mg, 2.8mmol, 2.5eq), react at room temperature for 4h. After the reaction was finished, the solvent was removed under red...

Embodiment 1-10

[0121] Embodiment 1-10, compound 1-(4-(hydroxycarbamoyl) benzyl)-N-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide ( QZ010) preparation.

[0122]

[0123] Dissolve 2-hydroxynicotinic acid (181mg, 1.3mmol, 1eq) and N,N'-carbonyldiimidazole (CDI, 211mg, 1.3mmol, 1eq) in DMF (5ml), react at 40°C for 30min, then add 1,8-diazabicycloundec-7-ene (DBU, 396mg, 2.6mmol, 1eq) and tert-butanol (193mg, 2.6mmol, 2eq) were reacted at 60°C for 12h. After the reaction, the solvent was removed under reduced pressure, extracted with ethyl acetate and water, and passed through a silica gel column after conventional treatment to obtain the intermediate tert-butyl 2-oxo-1,2-dihydropyridine-3-carboxylate (215 mg, 1.1 mmol).

[0124] Take the intermediate 2-oxo-1,2-dihydropyridine-3-carboxylic acid tert-butyl ester (215mg, 1.1mmol, 1eq) and dissolve it in anhydrous acetone (50ml), add 4-bromomethylbenzoic acid methyl Ester (252mg, 1.1mmol, 1.0eq) and K 2 CO 3 (304mg, 2.2mmol, 2eq),...

Embodiment 2

[0134] Example 2. Detection of IDO1 inhibitory activity of some compounds of the present invention

[0135]The plasmid construction containing human IDO1 gene in the present invention, the amplification and expression in Escherichia coli, and extraction and purification are all carried out according to the method reported by Christopher etc. (Austin, C.J., et al. (2004). Protein Expr Purif37 (2): 392-398.). The compound synthesized by the present invention is detected according to the following method: add 50 mM potassium phosphate buffer (PH 6.5), 10 mM sodium ascorbate, 10 μM methylene blue, 100 μg / ml catalase, 200 μM L-tryptophan in a 96-well plate, and different concentrations of inhibitors. The concentrations of inhibitors were set at 3.2805, 10.935, 36.45, 121.5, 405, 1350, 4500, 15000, 50000 nM. After incubating at 37°C for 5 minutes, IDO1 enzyme was added and reacted at 37°C for 30 minutes. Afterwards, 30% (w / v) trichloroacetic acid was added to terminate the reacti...

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PUM

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Abstract

The invention discloses a class of six-membered ring formamide compounds represented by formulas (I)-(II), a medicinal derivative and a hydrate thereof, a composition containing the six-membered ringformamide compound, and a preparation method of the six-membered ring formamide compound. The invention also discloses applications of the six-membered ring formamide compound as an IDO and HDAC double-target inhibitor in treatment of malignant tumors, improvement of the treatment effects of the current IDO and HDAC single-target small-molecule anti-cancer drugs, and reduction of the toxic and side effects of the IDO and HDAC single-target small-molecule anti-cancer drugs. The invention also discloses applications of the compound in prevention and treatment of diseases with pathological characteristics of IDO-mediated kynurenine metabolic pathway, wherein the diseases comprise cardiovascular diseases, autoimmune diseases, neuritis diseases, Alzheimer's disease, depression, virus infectionand the like.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a six-membered ring carboxamide compound and a synthesis method and application thereof. Background technique [0002] Epigenetic changes, including histone modification and DNA methylation, play a crucial role in the pathogenesis of many diseases, including cancer. Histone acetylation modification is one of the important ways of covalent modification of histone and one of the important molecular mechanisms to regulate epigenetic phenomena. Its acetylation level is controlled by histone acetyltransferase (HAT) and histone Acetylase (Histone Deacetylase, HDAC) coordinated control (Jaenisch, R. et al. Nat Genet. 2003, 33 Suppl, 245-54). Generally speaking, the function of HATs is to acetylate core histones, resulting in the electrical neutralization of histones, presenting a more open, transcribable chromatin active structure; while the function of HDACs is to deacetylate and repress tran...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/66C07D213/64C07C259/10C07D213/82C07D405/12C07D249/14A61P35/00A61P35/02A61P35/04A61P37/06A61P29/00A61P25/00A61P25/28A61P25/24A61P31/12A61P9/00A61K31/4412A61K31/443A61K31/44A61K31/36A61K31/166A61K31/4196
CPCC07D317/66C07D213/64C07C259/10C07D213/82C07D405/12C07D249/14A61P35/00A61P35/02A61P35/04A61P37/06A61P29/00A61P25/00A61P25/28A61P25/24A61P31/12A61P9/00
Inventor 章涵堃逄秀凤刘明耀邱子梁冯娟娟孙湘柏
Owner EAST CHINA NORMAL UNIV
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