Sulfonamide compound with tetrahydroquinoline as core and preparation method and application of sulfonamide compound

A technology of tetrahydroquinoline and sulfonamide, which can be applied in the directions of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., and can solve problems such as being in the initial stage.

Active Publication Date: 2019-08-02
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Prospects In recent years, research on NLRP3 inflammasome and its inhibitors has made some progress. However, most inhibitors exert therapeutic effects by targeting the downstream products of NLRP3 inflammasome activation, and directly target the specific inhibitors of NLRP3. Research is still in its early stages

Method used

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  • Sulfonamide compound with tetrahydroquinoline as core and preparation method and application of sulfonamide compound
  • Sulfonamide compound with tetrahydroquinoline as core and preparation method and application of sulfonamide compound
  • Sulfonamide compound with tetrahydroquinoline as core and preparation method and application of sulfonamide compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1 synthetic compound III

[0064]Weigh 7-nitrotetrahydroquinoline (48g, 0.27mol) in a reaction flask, add 100mL of dichloromethane and triethylamine (74.8mL, 0.54mol) to it in turn, stir for 15min under ice bath, dropwise add Methanesulfonyl chloride (21 mL, 0.27 mol), after stirring for 1 h, returned to room temperature and reacted until TLC monitored that the starting material disappeared completely. Wash with dilute hydrochloric acid and saturated brine successively, collect the organic phase, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. Add 1g / 1mL of methanol to make slurry for 1h, and filter to obtain 62.9g of white solid, yield: 91.2%. 1 HNMR (300MHz, CDCl 3 )δ8.56(d,J=2.1Hz,1H),7.89(dd,J=8.4,2.2Hz,1H),7.31(d,J=8.2Hz,1H),3.87–3.84(m,2H), 3.03(s,3H),2.97(t,J=6.6Hz,2H),2.17–2.00(m,2H). 13 CNMR (75MHz, CDCl 3 )δ149.34, 140.33, 138.77, 133.03, 121.23, 119.81, 48.84, 41.79, 30.12, 24.34. HRMS (ESI) calcd for C 10 h ...

Embodiment 2

[0065] Embodiment 2 synthetic compound Ⅳ

[0066] Compound III (19 g, 74.2 mmol) was weighed into a reaction flask, and 60 mL of dichloromethane and 1.9 g of 10% palladium on carbon (10% Pd on carbon) were added thereto, and reacted at room temperature for 48 h under a hydrogen atmosphere, and the disappearance of raw materials was monitored by TLC. Filtrate through celite, remove the solvent under reduced pressure, and slurry with methanol (30 mL) to obtain 14 g of white solid with a yield of 83.3%. 1 H NMR (300MHz, CDCl 3 )δ7.11(d,J=2.0Hz,1H),6.90(d,J=8.1Hz,1H),6.45(dd,J=8.1,2.1Hz,1H),3.83–3.75(m,2H), 3.63(s,2H),2.89(s,3H),2.74(t,J=6.6Hz,2H),2.01–1.87(m,2H). 13 C NMR (75MHz, CDCl 3 )δ145.29, 137.48, 130.39, 118.65, 111.98, 108.82, 746.64, 38.35, 26.34, 22.29. HRMS (ESI) calcd for C 10 h 15 N 2 o 2 S[M+H] + 227.0849, found 227.0878. HPLC (10%–100% methanol in water), t R =9.43min, >97.60%.

Embodiment 3

[0067] Embodiment 3 synthetic compound Ⅰ-1

[0068] 4-cyano-N-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (Ⅰ-1)

[0069] Taking compound Ⅰ-1 as an example, weigh compound Ⅳ (200mg, 0.885mmol) into the reaction flask, add 14mL of dichloromethane and pyridine (71μL, 0.885mmol) in turn, and add 4-cyanobenzenesulfonyl chloride dropwise (178mg, 0.885mmol) in dichloromethane (6mL) was reacted at room temperature overnight, and the disappearance of the starting material was monitored by TLC. The reaction solution was successively washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Slurry with 5 mL of methanol and filter. Obtained off-white solid I-1147mg, yield: 42.5%.

[0070] 4-cyano-N-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)benzenesulfonamide (Ⅰ-1). Off-white solid, yield 42.5% , m.p.172.8-173.9°C. 1 H NM...

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Abstract

The invention discloses a sulfonamide compound with tetrahydroquinoline as a core and a preparation method and application of the sulfonamide compound. The sulfonamide compound with tetrahydroquinoline as the core is novel in structure and simple in preparation method, is capable of reducing mature secretion of interleukin IL-1beta by specifically inhibiting activation of NLRP3 inflammasome, thenalleviating inflammatory injury and improving inflammatory microenvironments, has remarkable anti-inflammation activity, and meanwhile has no conspicuous toxicity for THP-1 cells. The compound disclosed by the invention can be prepared as an anti-inflammation medicine for treating inflammation related diseases, including purpurin-related periodic syndromes, inflammatory intestine problems, chronicretardant lung diseases, diabetes, rheumatic arthritis, rheumatoid arthritis, gout, non-alcoholic fatty liver diseases, chronic kidney diseases, atherosclerosis, neurodegenerative diseases and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a sulfonamide compound whose mother nucleus is tetrahydroquinoline, a preparation method and application thereof. Background technique [0002] The inflammasome is a macromolecular multiprotein complex existing in the cytoplasm, which recognizes a variety of pathogenic microorganisms and endogenous danger signal molecules through pattern recognition receptors (PRR). As a component of innate immunity, inflammasome plays an important role in immune response. But abnormal activation of inflammasome can also cause many diseases such as type 2 diabetes, gout, atherosclerosis, Parkinson's syndrome, Alzheimer's disease, multiple sclerosis. The currently identified inflammasomes include NLRP1, NLRP2, NLRP3, AIM2 (absent inmelanoma 2) and NLRC4. Among them, NLRP3 is currently the most studied and mature type of inflammasome. The NLRP3 inflammasome is the most typical famil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/58A61K31/47A61P1/00A61P11/00A61P3/10A61P19/02A61P19/06A61P1/16A61P9/10A61P13/12A61P25/00A61P25/14A61P25/16A61P25/28
CPCC07D215/58A61P1/00A61P11/00A61P3/10A61P19/02A61P19/06A61P1/16A61P9/10A61P13/12A61P25/00A61P25/14A61P25/16A61P25/28
Inventor 徐莉莉狄斌代祯陈小意
Owner CHINA PHARM UNIV
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