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Compound with pyridoimidazole as parent nucleus as well as preparation method and application of compound

A technique for pyridimidazole and compounds, applied in the field of compounds whose mother core is pyridimidazole and its preparation, can solve the problems of large side effects and failure to become drugs, etc., reduce inflammatory damage, improve inflammatory microenvironment, and have simple preparation methods Effect

Pending Publication Date: 2022-04-15
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many compounds that can inhibit the NLRP3 pathway, some of them are targeting the signaling molecules in the middle and downstream of the pathway, not only affecting this pathway, but some are targeting NLRP3 itself, but have other biological activities at the same time, with huge side effects, and some are targeting NLRP3 itself and select Very good, like MCC950, but can't be a drug because of hepatotoxicity

Method used

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  • Compound with pyridoimidazole as parent nucleus as well as preparation method and application of compound
  • Compound with pyridoimidazole as parent nucleus as well as preparation method and application of compound
  • Compound with pyridoimidazole as parent nucleus as well as preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1 synthetic compound III

[0074] Weigh 3,4-diaminopyridine (8g, 0.0733mol) into the reaction flask, add 60ml of absolute ethanol and carbon disulfide (15.9ml, 0.264mol) to it in sequence, and react under reflux at 80°C for 4h. TLC monitors that the raw materials disappear. The reaction solution was cooled to room temperature, suction filtered, and the filter cake was washed with ethyl acetate, and dried to obtain 10.2 g of off-white solid, yield: 92.0%. 1 H NMR (300MHz, DMSO-d6) δ12.87(s, 2H), 8.37(d, J=1.0Hz, 1H), 8.23(d, J=5.4Hz, 1H), 7.16(dd, J=5.4, 1.0Hz,1H).

Embodiment 2

[0075] Embodiment 2 synthetic compound IV-1

[0076] 2-(Benzylthio)-3-hydro-imidazo[4,5-c]pyridine (IV-1)

[0077] Weigh compound III (500mg, 3.31mmol) into the reaction flask, add 5ml of N,N-dimethylformamide, anhydrous sodium carbonate (701.04mg, 6.61mmol) to it successively, heat and react at 40°C for 1h, then slowly drop Benzyl bromide (412 μl, 3.47 mmol) was added, and the reaction was continued for 4 h, and the disappearance of the starting material was monitored by TLC. The reaction solution was cooled to room temperature, poured into a separatory funnel, diluted with a large amount of water, extracted with n-butanol, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and used a dichloromethane / methanol column Separation and purification by chromatography gave 519.6 mg of white solid, yield: 65.11%.

[0078] 2-(Benzylthio)-3-hydro-imidazo[4,5-c]pyridine (IV-1). White solid, yield: 65.1...

Embodiment 3

[0079] Embodiment 3 synthetic compound IV-2

[0080] 2-((2-fluorobenzyl)thio)-3-hydrogen-imidazo[4,5-c]pyridine (IV-2). The synthesis method is the same as in Example 2, and compound III (500mg, 3.31mmol ), anhydrous sodium carbonate (701.04mg, 6.61mmol), and 2-fluorobenzyl bromide (419μl, 3.47mmol) were used as raw materials to obtain 527.6mg of a white solid with a yield of 61.52%. 1 H NMR (300MHz, DMSO-d6) δ13.18(s, 1H), 8.77(s, 1H), 8.18(d, J=5.7Hz, 1H), 7.58(td, J=7.7, 1.8Hz, 1H) ,7.50(d,J=4.9Hz,1H),7.39–7.29(m,1H),7.27–7.18(m,1H),7.15(td,J=7.4,1.3Hz,1H),4.64(s,2H ).

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Abstract

The invention discloses a compound with pyridoimidazole as a parent nucleus as well as a preparation method and application of the compound. The compound with the mother nucleus being pyridoimidazole is novel in structure and simple in preparation method, can specifically inhibit activation of NLRP3 inflammasomes and reduce mature secretion of interleukin IL-1beta, so that inflammatory injury is relieved, the inflammatory microenvironment is improved, and the compound has remarkable anti-inflammatory activity and has no obvious toxicity to THP-1 cells. The compound provided by the invention can be prepared into an anti-inflammatory drug and used for treating inflammation-related diseases, including rheumatic arthritis, rheumatoid arthritis, inflammatory intestinal diseases, gout, atherosclerosis, non-alcoholic fatty liver diseases, cold pyraline-related periodic syndromes, chronic kidney diseases, diabetes mellitus, neurodegenerative diseases and the like.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a compound whose parent nucleus is pyridoimidazole, a preparation method and application thereof. Background technique [0002] The inflammasome is a complex of proteins that is activated when cells are infected or stimulated. The innate immune system recognizes pathogen-associated molecular patterns (PAMP) or damage-associated molecular patterns (DAMP) through pattern recognition receptors (PRR). A variety of PRRs have been discovered, including the nucleotide-binding oligomerization domain (NOD)-like receptor (NOD-like receptor, NLR). The NLR family includes many members, among which the NOD like receptor containing pyrin domain 3 (NLRP3) is the most thoroughly studied. [0003] NLRP3 contains three domains: pyrin domain (PYD), nucleotide binding domain (nucleoside triphosphate domain, NACHT), and leucine-rich domain (LRR). When NLRP3 is activated, oligomerization occurs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/437A61K31/444A61K31/5377A61K31/496A61P37/06A61P19/02A61P1/00A61P19/06A61P9/10A61P1/16A61P13/12A61P3/10A61P25/28A61P25/16A61P29/00A61P25/14
CPCC07D487/04A61P37/06A61P19/02A61P1/00A61P19/06A61P9/10A61P1/16A61P13/12A61P3/10A61P25/28A61P25/16A61P29/00A61P25/14
Inventor 徐莉莉狄斌李冰艳江程李沛
Owner CHINA PHARM UNIV
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