Medical application of benzenesulfonamide compound, and pharmaceutical composition

A technology of benzenesulfonamides and compounds, applied in the direction of drug combinations, amide active ingredients, antipyretics, etc., can solve the problems of large side effects and weak activity, and achieve the effect of prolonging the long-term survival rate

Active Publication Date: 2020-12-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are only a handful of STING small molecule inhibitors reported in the literature, with weak activity and large side effects (CellReports 2018, 25, 3405–3421; ACS Med.Chem.Lett, 2019, 10(1), 92-97)

Method used

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  • Medical application of benzenesulfonamide compound, and pharmaceutical composition
  • Medical application of benzenesulfonamide compound, and pharmaceutical composition
  • Medical application of benzenesulfonamide compound, and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] N-(3-((4-fluorophenyl)sulfonylamino)-4-hydroxyphenyl)-[1,1'-biphenyl]-4-carboxamide (Compound I)

[0127]

[0128] Compound 1 (2.00g, 13.0mmol) and pyridine (1.54g, 19.5mmol, 1.57mL) were dissolved in 40mL of dichloromethane, and 4-fluorine dissolved in 20mL of dichloromethane was added dropwise at 0°C Benzenesulfonyl chloride 1A (3.04g, 15.68mmol), mixed and stirred at 25°C for 12 hours. Subsequently, the reaction was identified to be complete by thin layer chromatography (TLC), and the mobile phase was petroleum ether:ethyl acetate=2:1. The solvent was evaporated and removed under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1~2:1, V / V) to obtain a pale yellow solid product Compound 2 (2.74g, 67.6% yield). 1 HNMR: (DMSO-d 6 ,400MHz)δ8.04(d,J=2.4Hz,1H),7.94~7.92(m,1H),7.83~7.80(m,2H),7.41~7.37(m,2H),6.89(d,J= 8.8Hz,1H).LCMS(m / z):312.02[M+H] + .

[0129] Compound 2 (1...

Embodiment 2

[0134] N-(3-((4-fluorophenyl)sulfonylamino)-4-methoxyphenyl)-[1,1'-biphenyl]-4-carboxamide (Compound II)

[0135]

[0136] Compound 6 (0.54g, 3.2mmol), pyridine (0.5mL) was added in dichloromethane (10mL), and 4-fluorobenzenesulfonyl chloride (1A: 0.744g, 3.84mmol) was added dropwise in dichloromethane ( 10mL) solution, after dropping, react at room temperature for 8h. The solvent was evaporated under reduced pressure, ethyl acetate (50mL) and water (20mL) were added, shaken evenly to separate the liquids, the organic phase was washed with 1N HCl (10mL), water (20mL) and saturated brine (20mL) respectively, anhydrous Na 2 SO 4 Dry, filter, evaporate the solvent under reduced pressure to obtain a residue, and the crude product is purified by silica gel column chromatography (mobile phase is petroleum ether:ethyl acetate=10:1~2:1, V / V) to obtain a light yellow solid product compound 7 (0.74 g, 71%).

[0137] Compound 7 (0.5g, 1.53mmol), 10%Pd / C (50mg) was added in MeOH (20...

Embodiment 3

[0140] 4-([1,1'-biphenyl]-4-carboxamido)-2-((4-fluorophenyl)sulfonylamino)phenylacetate (Compound V)

[0141]

[0142]

[0143] Compound I (200mg, 0.43mmol) prepared in Example 1 was dissolved in THF (5mL), pyridine (52μL, 0.65mmol) was added, and acetyl chloride (37μL, 0.52mmol) was added dropwise at room temperature, and reacted at room temperature for 10h. Quenched with water (10 mL), extracted with EtOAc (30 mL), the organic phase was washed successively with 1N HCl (10 mL), water (10 mL) and saturated brine (10 mL), anhydrous Na 2 SO 4 After drying, filtering, and evaporating the solvent under reduced pressure, a white solid was obtained, which was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain a white solid, compound V (76 mg, 35%). 1 H NMR (300MHz, DMSO-d 6 )δppm 10.39(s,1H),10.01(s,1H),8.06(d,J=8.3Hz,2H),7.96(d,J=2.2Hz,1H),7.86-7.8(m,4H),7.77 (d,J=7.4Hz,2H),7.62(dd,J=8.8,2.3Hz,1H),7.52(dd,J=7.4,7.4Hz,2H),7.44(d,J=5.3Hz,1H) ,7.40(dd,J=7...

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Abstract

The invention discloses medical application of a benzenesulfonamide compound, and a pharmaceutical composition, and particularly relates to compounds shown as formulas I to V or pharmaceutically acceptable salts or solvates of the compounds. The compounds or the pharmaceutically acceptable salts or solvates of the compounds can be used for preparing STING inhibitors or drugs for inhibiting STING signal path activation and drugs for preventing or treating STING-mediated diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to the medical use and pharmaceutical composition thereof of benzenesulfonamide compounds or pharmaceutically acceptable salts or solvates thereof, which can act on transmembrane protein 173 (TMEM173), also known as STING ( stimulators of interferon genes) and inhibit their signaling pathways. Therefore, the compounds can be used to prepare medicines for preventing or treating diseases mediated by STING. Background technique [0002] The activation of the body's innate immune system is mediated by the recognition of non-self pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) by pattern recognition receptors (PRRs) expressed on the cell membrane and in the cytoplasm. After recognizing PAMPs, PRRs activate the conduction of downstream immune signals, promote the release of inflammation and immune cytokines, and further activate the body's ada...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/18A61P29/00A61P3/10A61P9/00A61P19/02A61P17/06A61P37/02A61P1/16A61P9/10
CPCA61K31/18A61P29/00A61P3/10A61P9/00A61P19/02A61P17/06A61P37/02A61P1/16A61P9/10
Inventor 王琛洪泽余文颖孙宏斌梅家豪李晨辉刘星孙立柳军
Owner CHINA PHARM UNIV
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