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Amide compound and medical application thereof as STING inhibitor

A technology of amide compounds and solvates, which is applied in the field of biomedicine and can solve problems such as weak activity and large side effects

Active Publication Date: 2021-02-26
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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  • Amide compound and medical application thereof as STING inhibitor
  • Amide compound and medical application thereof as STING inhibitor
  • Amide compound and medical application thereof as STING inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] N-(3-((4-fluorophenyl)sulfonylamino)-4-hydroxyphenyl)-3'-sulfamoyl[1,1'-biphenyl]-4-carboxamide (Compound A-1 )

[0128]

[0129]

[0130] A THF (2 mL) solution of compound I-0 (3-bromobenzenesulfonyl chloride) (610 mg, 2.39 mmol) was added dropwise into aqueous ammonia (6 mL), and reacted at room temperature for 5 h. The reaction solution was extracted with EtOAc (20mL), and the organic phase was washed with water (10mL) and saturated brine (10mL) successively, and anhydrous Na 2 SO 4 After drying, filtering, and evaporating the solvent under reduced pressure, the compound I-1 (534 mg, 95%) was obtained as a white solid.

[0131] Compound I-1 (238mg, 1.01mmol), p-methoxycarbonylphenylboronic acid (200mg, 1.11mmol), anhydrous K 2 CO 3 (279mg, 2.02mmol), Pd(PPh 3 ) 4 (58 mg, 0.05 mmol) was added to Toluene (Tol) (10 mL) and MeOH (2 mL), and reacted for 3 h under nitrogen atmosphere at 80°C. Cool at room temperature, filter and wash the filter cake with EtOAc...

Embodiment 2

[0138] N-(3-((4-fluorophenyl)sulfonylamino)-4-hydroxyphenyl)-4'-methoxy-3'-sulfamoyl[1,1'-biphenyl]-4- Formamide (Compound A-2)

[0139]

[0140] With reference to the method of Example 1, 3-bromobenzenesulfonyl chloride was replaced by 2-methoxy-5-bromobenzenesulfonyl chloride to obtain compound A-2: 1 H NMR (300MHz, DMSO-d 6)δppmδ10.10(s,1H),9.38(s,1H),9.27(s,1H),8.05(d,J=2.3Hz,2H),8.02(s,1H),7.97(dd,J=8.6 ,2.3Hz,1H),7.87-7.73(m,4H),7.70(d,J=2.2Hz,1H),7.42(dd,J=8.8,2.4Hz,1H),7.32-7.38(m,3H) ,7.17(s,2H),6.70(d,J=8.8Hz,1H),3.97(s,3H).ESI-MS:m / z 570.1[M-H] - .

Embodiment 3

[0142] 4'-(3-((4-fluorophenyl)sulfonylamino)-4-hydroxyphenyl)carbamoyl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester (Compound A -3)

[0143]

[0144] Referring to the method of Example 1, replace I-3 with 4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-carboxylic acid to obtain compound A-3: 1 H NMR (300MHz, DMSO-d 6 )δppm 10.15(s,1H),9.41(s,1H),9.31(s,1H),8.11-8.03(m,4H),7.91(m,4H),7.82(dd,J=8.8,5.2Hz, 2H), 7.71(d, J=2.2Hz, 1H), 7.43(dd, J=8.6, 2.2Hz, 1H), 7.33-7.39(m, 2H), 6.70(d, J=8.7Hz, 1H), 3.89(s,3H).ESI-MS: m / z519.1[M-H] - .

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Abstract

The invention discloses an amide compound and medical application thereof as an STING inhibitor, and particularly relates to a compound shown as a formula I or a formula II or pharmaceutically acceptable salt or ester or solvate thereof, which can be used for preparing the STING inhibitor or medicine for inhibiting STING signal path activation and preparing medicine for preventing or treating STING mediated diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine, in particular to a class of novel amide compounds or pharmaceutically acceptable salts or solvates thereof, which can act on transmembrane protein 173 (TMEM173), also known as STING (stimulator of interferon gene ), as well as preparation and medical use thereof, the present invention also relates to the use of such compounds in the preparation of medicines for preventing or treating STING-mediated diseases. 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 adaptive immune system to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/21C07C311/29C07D317/60C07D319/18C07D333/24C07D241/12C07D239/26C07D215/48C07D271/12C07D271/06C07D277/66C07C317/44C07D295/26C07C311/08C07C311/11C07C311/09C07D333/34C07D213/71C07C233/80C07D333/38C07D307/68C07C311/51C07C275/40A61P31/00A61P29/00A61P37/02A61P35/00A61P35/02A61P31/06A61P31/22A61P31/20A61P31/14A61P3/00A61P5/50A61P3/10A61P3/06A61P9/10A61P9/06A61P9/12A61P9/00A61P25/00A61P13/12A61P27/02A61P1/16A61P19/02A61P21/00A61P1/00A61P1/18A61P15/00A61P11/00A61P11/06A61P17/06A61P37/06A61P17/00
CPCC07C311/21C07C311/29C07D317/60C07D319/18C07D333/24C07D241/12C07D239/26C07D215/48C07D271/12C07D271/06C07D277/66C07C317/44C07D295/26C07C311/08C07C311/11C07C311/09C07D333/34C07D213/71C07C233/80C07D333/38C07D307/68C07C311/51C07C275/40A61P31/00A61P29/00A61P37/02A61P35/00A61P35/02A61P31/06A61P31/22A61P31/20A61P31/14A61P3/00A61P5/50A61P3/10A61P3/06A61P9/10A61P9/06A61P9/12A61P9/00A61P25/00A61P13/12A61P27/02A61P1/16A61P19/02A61P21/00A61P1/00A61P1/18A61P15/00A61P11/00A61P11/06A61P17/06A61P37/06A61P17/00
Inventor 孙宏斌王琛尤燕平孙立洪泽潘燕红隋齐邦臧永军袁浩亮温小安许庆龙柳军
Owner CHINA PHARM UNIV
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