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NLRP3 inflammasome inhibitor and preparation method and application thereof

A pharmacy and compound technology, applied in the field of NLRP3 inflammasome inhibitors and its preparation, can solve problems such as potential safety hazards, unclear off-target effects, and unclear elucidation of the specific mechanism of action of MCC950

Inactive Publication Date: 2020-10-30
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the existing literature reports are not clear about the specific mechanism of action of MCC950, and it is not clear whether the substance has potential off-target effects
Although it has been reported in the literature that MCC950 will undergo an oxidation reaction to produce the main metabolite I under the action of human liver microsomes in vitro, however, based on the complex metabolic environment in the human body, it is speculated that the furan ring and sulfamoylurea Linked fragments may be metabolized by CYP450 enzymes in vivo to produce active intermediates II and III respectively (eg figure 1 shown)
Intermediate II can undergo 1,2-addition or 1,4-addition to key amino acid residues in the body to form conjugates with biomacromolecules; isocyanate III can also form biomacromolecules such as glutathione Conjugates; and then produce a series of metabolites, which lead to the inactivation of drug molecule metabolism, and even liver toxicity, which may lead to safety hazards

Method used

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  • NLRP3 inflammasome inhibitor and preparation method and application thereof
  • NLRP3 inflammasome inhibitor and preparation method and application thereof
  • NLRP3 inflammasome inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Preparation of (1,2,3,5,6,7-hexahydro-s-indan-4-yl) tert-butyl sulfamoylcarbamate (LW-01-7-1)

[0058] To a stirred solution of chlorosulfonyl isocyanate (CSI) (0.3ml, 2.65mmol) in anhydrous dichloromethane (3mL) was added tert-butanol (0.26, 2.65mmol) at 0°C, and after reacting for 30 minutes, the resulting solution was and triethylamine (0.375 mL, 2.65 mmol) were slowly added to 2 mL of a dichloromethane solution containing 1 equivalent of 1,2,3,5,6,7-hexahydro-s-indan-4-amine. The resulting reaction solution was warmed up to room temperature and reacted for 2 hours. The reaction mixture was diluted with 30 mL of dichloromethane, washed with 0.1N HCl and water. The organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo to give crude product. The residue was purified by silica gel column chromatography (PE / EA: 3 / 1).

Embodiment 2

[0059] Preparation of Example 2 LW-01-7-2

[0060] In order to remove the Boc protecting group, the above product (LW-01-7-1) was reacted in 6 mL of HCl:EA=1:2 (volume ratio) mixture at room temperature for 1 hour. It was then concentrated under vacuum. After neutralization with ammonia, the reaction mixture was diluted with 30 mL of dichloromethane and washed with water. The organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo to give crude product. The residue was purified by silica gel column chromatography (PE / EA: 2 / 1) to obtain the product (332 mg, 49.7%). The structural formula of the compound LW-01-7-2 is the formula (2) above.

Embodiment 3

[0061] Example 3 3-Bromo-N-(N-(1,2,3,5,6,7-hexahydro-s-indan-4-yl)sulfamoyl)benzamide (LW-01-18 -1)

[0062] Under nitrogen protection, 3-bromobenzoic acid (40mg, 0.2mmol) and CDI (65mg, 0.4mmol) were dissolved in THF (2mL), heated to reflux at 70°C for 45 minutes, cooled to room temperature and added LW-01-7 -2 (80 mg, 0.32 mmol) and DBU (0.09 mL, 0.6 mmol). The mixture was stirred at ambient temperature for 22 hours. The reaction mixture was diluted with 30 mL of dichloromethane, washed with 0.1N HCl and water. Na for organic layer 2 SO 4 Dry, filter, and concentrate in vacuo to give crude product. Purification by silica gel column chromatography (DCM / MeOH: 70 / 1) gave the product as a white solid (96 mg, 64%). 1 H NMR(400MHz,DMSO)δ12.03(s,1H),9.70(s,1H),8.04(s,1H),7.89(d,J=7.4Hz,1H),7.81(d,J=7.6Hz ,1H),7.48(t,J=7.6Hz,1H),7.00(s,1H),2.78(d,J=8.1Hz,8H),1.92–1.81(m,4H). 13 C NMR (151 MHz, DMSO) δ 164.85, 143.93, 141.05, 135.81, 135.12, 131.27, 131.14, 128.52, 127.64, 12...

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Abstract

The invention relates to a class of 1, 2, 3, 5, 6, 7 hexahydrosymmetric indacene compounds containing one or more substituents., pharmaceutically acceptable salts, esters or hydrates thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and an application of the compounds as a novel NLRP3 inflammasome inhibitor in preparation of drugs for preventing and / or treating diseases related to NLRP3 inflammasome.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to an NLRP3 inflammasome inhibitor and its preparation method and application. Background technique [0002] Innate immunity is the first barrier of the body, which can eliminate foreign pathogens and guide the body to produce an effective adaptive immune response. The mutual recognition and interaction between pattern recognition receptors (PRRs) on the surface of innate immune cells and pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic organisms is the key to initiating innate immunity. NLR is an important member of the cytoplasmic PRR family. It is an intracellular sensory molecule and plays a unique role in innate immunity. Among them, NLRP is the largest subfamily of NLP, with a total of 14 family members and a characteristic PYD effector domain. [0003] The NLRP3 inflammasome, a multiprotein complex composed of the innate immune receptor NLRP3, the street p...

Claims

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Application Information

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IPC IPC(8): C07C307/10C07D215/48C07D275/03C07D239/28C07D307/68C07D237/24C07C237/24C07C237/38C07C311/20A61K31/166A61K31/325A61K31/425A61K31/505A61K31/47A61K31/50A61K31/18A61P29/00A61P19/06A61P3/10A61P9/10A61P25/28
CPCC07C307/10C07D215/48C07D275/03C07D239/28C07D307/68C07D237/24C07C237/24C07C237/38C07C311/20A61P29/00A61P19/06A61P3/10A61P9/10A61P25/28C07C2603/10C07C2601/02C07C2601/14
Inventor 叶娜郑龙太镇学初李婉婉曹忠强
Owner SUZHOU UNIV
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