Macrocyclic sulfonamide derivatives useful as NLRP3 inhibitors

A monocyclic, compound technology for the treatment and prevention of medical conditions and diseases, the field of macrocyclic sulfonamides, which can solve problems such as limited efficacy and non-specificity

Pending Publication Date: 2022-05-27
INFLAZOME LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited potency and have non-specific

Method used

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  • Macrocyclic sulfonamide derivatives useful as NLRP3 inhibitors
  • Macrocyclic sulfonamide derivatives useful as NLRP3 inhibitors
  • Macrocyclic sulfonamide derivatives useful as NLRP3 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[2056] Example 1: 16,16-Dimethyl-6-(propan-2-yl)-18-oxa-11λ 6 -Thia-10,15,20,24-tetraaza-tetracyclo[17.3.1.1 12,15 .0 2,7 ]Tetracos-1(22),2(7),3,5,12(24),13,19(23),20-octene-9,11,11-trione

[2057]

[2058] DMAP (70.8 mg, 0.580 mmol) and EDC (111 mg, 0.580 mmol) were added to 2-(2-isopropyl-6-(2-(2-methyl-2-(3-sulfamoyl-1H- Pyrazol-1-yl)propoxy)pyridin-4-yl)phenyl)acetic acid (Intermediate C2) (137 mg, 0.290 mmol) in DMF (2 mL), the reaction was stirred at room temperature for 18 h. The crude product was purified by acidic preparative HPLC (50-80% MeCN in water) to give the title compound (10.78 mg, 8%) as a flocculent white solid.

[2059] LCMS m / z 455.2(M+H) + (ES + ); 453.2 (M-H) - (ES - ).

[2060] 1 H NMR (DMSO-d 6 )δ11.93(s, 1H), 8.22(d, J=5.1Hz, 1H), 8.03(s, 1H), 7.38-7.32(m, 1H), 7.29(t, J=7.6Hz, 1H), 6.94-6.90(m, 1H), 6.88(d, J=5.1Hz, 1H), 6.71(s, 1H), 5.73(s, 1H), 4.50(s, 2H), 3.41-3.35(m, 2H) , 2.97-2.92 (m, 1H), 1.66 (s, 6H), 1.17 (d, J=6.7Hz, 6H)....

Embodiment 6

[2069] Example 6: 16-Fluoro-19,19-dimethyl-21-oxa-14λ 6 -Thia-13,18,23,27-tetraazapentacyclo[20.3.1.1 15,18 .0 2,10 .0 5,9 ] Heptadecan-1(25),2,4,9,15(27),16,22(26),23-octene-12,14,14-trione

[2070]

[2071]2-(5-(2-(2-(4-Fluoro-3-sulfamoyl-1H-pyrazol-1-yl)-2-methylpropoxy)pyridin-4-yl)-2, 3-Dihydro-1H-inden-4-yl)acetic acid (Intermediate C6) (45 mg, 0.092 mmol) was dissolved in NMP (2 mL), to which was added HATU (52 mg, 0.137 mmol) and DIPEA (48 μL, 0.275 mmol) ). The reaction was stirred at room temperature for 18 h. The mixture was purified by basic preparative HPLC (20-50% MeOH in water) to give the title compound (8 mg, 18%) as a white solid.

[2072] LCMS m / z 471.4(M+H) + (ES + ).

[2073] 1 H NMR (DMSO-d 6 )δ12.12(s, 1H), 8.28(d, J=4.2Hz, 1H), 8.20(d, J=5.1Hz, 1H), 7.19(d, J=7.5Hz, 1H), 6.90(d, J=7.5Hz, 1H), 6.86(dd, J=5.2, 1.4Hz, 1H), 5.85(s, 1H), 4.53(s, 2H), 3.38(s, 2H), 2.93(t, J=7.4 Hz, 2H), 2.80 (t, J=7.5Hz, 2H), 2.03 (p, J=7.5Hz, 2H), 1.63 (s, ...

Embodiment 17

[2074] Example 17: 17-(2-Hydroxypropan-2-yl)-22-oxa-14λ 6 -Thia-13,24-diazapentacyclo-[21.3.1.1 15,19 .0 2,10 .0 5,9 ] Octacos-1(26),2,4,9,15,17,19(28),23(27),24-nonene-12,14,14-trione

[2075]

[2076] CDI (57 mg, 0.352 mmol) was dissolved in MeCN (10 mL), to which was added 2-(5-(2-(3-(2-hydroxypropan-2-yl)-5-sulfamoylphenethoxy) )pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate C17) (192 mg, 0.377 mmol). The mixture was stirred at room temperature for 1 h. A solution of DBU (53 μL, 0.355 mmol) in MeCN (10 mL) was then added and the mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and the resulting residue was purified by acidic preparative HPLC (35-65% MeCN in water) to give the title compound (6 mg, 3%) as a white solid.

[2077] LCMS m / z 493.4(M+H) + (ES + ).

[2078] 1 H NMR (CDCl 3 )δ7.97-7.87(m, 2H), 7.85-7.73(m, 2H), 7.47(s, 1H), 7.29(s, 1H), 7.06(d, J=7.8Hz, 1H), 6.69(d , J=5.2Hz, 1H), 6.46(br ...

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Abstract

The present invention relates to macrocyclic compounds, such as macrocyclic sulfonamides. The invention also relates to related salts, solvates, prodrugs and pharmaceutical compositions, and to the use of these compounds, most particularly by NLRP3 inhibition, in the treatment and prophylaxis of medical conditions and diseases.

Description

technical field [0001] The present invention relates to macrocyclic compounds, such as macrocyclic sulfonamides. The present invention also relates to related salts, solvates, prodrugs and pharmaceutical compositions, and to the use of these compounds in the treatment and prevention of medical conditions and diseases, most particularly through NLRP3 inhibition. Background technique [0002] The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process and its abnormal activity is implicated in genetic disorders such as cold inflammation It is pathogenic in hormone-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis. [0003] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds an apoptosis-associated speck-like protei...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/18C07D513/08C07D513/22C07D515/18A61P29/00A61K31/439A61K31/5377A61K31/496A61K31/504
CPCC07D513/18C07D513/08C07D513/22C07D515/18A61P29/00C07D515/08C07D515/22
Inventor M·库珀D·米勒A·麦克劳德S·汤姆J·香农C·A·因塞蒂-普拉迪洛斯C·G·麦克弗森
Owner INFLAZOME LTD
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