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Benzamide derivatives as cgas-sting pathway agonists

A phenyl, hydrate technology, applied in the field of benzamide derivatives as CGAS-STING pathway agonists, can solve problems such as failure, in vivo biological activity and pharmacological properties to be determined

Pending Publication Date: 2021-06-01
BARUCH S BLUMBERG INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

5,6-dimethylxanthenone-4-acetic acid (DMXAA) was originally discovered and developed as a vascular disruptor with anti-tumor activity in various mouse models, failed in (Conlon et al., 2013)
However, the in vivo biological activities and pharmacological properties of these three small molecule human STING agonists remain to be determined (Liu et al., 2017)(Sali et al., 2015)

Method used

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  • Benzamide derivatives as cgas-sting pathway agonists
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  • Benzamide derivatives as cgas-sting pathway agonists

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Experimental program
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preparation example Construction

[0522] Preparation of compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection and selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., "Protecting Groups in Organic Synthesis", 2nd Ed. (Wiley & Sons, 1991). The entire disclosure thereof is hereby incorporated by reference for all purposes.

[0523] The reactions or methods described in the present invention can be carried out in suitable solvents which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are generally substantially nonreactive with the reactants, intermediates and / or products at the temperatures at which the reactions are carried out, ie, temperatures that may range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one ...

Embodiment 1

[0540]Example 1: N-(naphthalene-1-yl)benzo[d][1,3]dioxazole-5-carboxamide: pipecolic acid (0.0829g, 0.499mmol), 1-aminonaphthalene (0.080 g, 0.5586mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU, 0.2068g, 0.5453mmol) were dissolved in N,N-Dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.26 mL). The mixture was stirred at 22°C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine and the mixture was concentrated under vacuum and purified using normal phase chromatography (12g Isco silica gel column, ethyl acetate-hexane, 0-30%) to give a white solid (0.0562g, 38.65%). 1 H NMR (300MHz, CDCl 3 ): δ8.05-8.02(m, 2H), 7.91-7.89(m, 2H), 7.74(d, J=7.5Hz, 1H), 7.55-7.48(m, 5H), 6.94(d, J=9Hz , 1H), 6.09(s, 2H, OCH 2 O). C 18 h 13 NO 3 MS calculated for, 291.09; observed, (M+H) ...

Embodiment 2

[0542] Example 2: N-(naphthalene-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamide: 1,4-benzyldioxane-6 -Carboxylic acid (0.0860g, 0.4773mmol), 1-aminonaphthalene (0.0752g, 0.525mmol) and (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Urea (hexafluorophosphate) (HBTU, 0.1991 g, 0.525 mmol) was dissolved in N,N-dimethylformamide (DMF, 1 mL) and treated with N,N-diisopropylethylamine (0.25 mL). The mixture was stirred at 22°C for 18 hours. Ethyl acetate (20 mL) was added to dilute the mixture, and the mixture was washed with HCl (5 mL, 1 M, twice), saturated NaHCO 3 The solution was washed with saturated brine, then concentrated in vacuo, and subjected to normal phase chromatography (12 g Isco silica gel column, ethyl acetate-hexane, ) to give a white solid (0.0737g, 50.58%). 1 H NMR (300MHz, CDCl 3 ): δ8.10-8.05(m, 2H), 7.90-7.89(m, 2H), 7.73(d, J=6Hz, 1H), 7.54-7.52(m, 5H), 7.00-6.98(m, 1H) , 4.34(s, 4H, OCH 2 CH 2 O). C 19 h 15 NO 3 MS calculated for, 305.11; obse...

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Abstract

Pharmaceutical compositions of the invention comprise functionalized benzamide derivatives useful as cyclic GMP-AMP synthase- Stimulator of interferon gene (cGAS-STING) pathway agonists, and useful for treating viral diseases and boost antitumor immunity.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 740,210, filed October 2, 2018; the entire contents of which are hereby incorporated by reference. Background technique [0003] Vertebrate genomes encode arrays of proteins called pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns following infection with microorganisms, thereby activating pro-inflammatory cytokine responses (Akira et al., 2006). This innate cytokine response not only suppresses the proliferation of microorganisms and limits their dissemination, but also induces a stronger adaptive immune response that ultimately controls microbial infection (Chang et al., 2012; Iwasaki and Medzhitov, 2015). Stimulator of interferon genes (STING) is a transmembrane protein located on the membrane of the endoplasmic reticulum (ER) and acts as a sensor for intracellular bacterial production or by cytoplasmic D...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D317/68C07D241/24C07D231/56C07D405/06C07C235/56C07C233/65C07C2602/08C07C233/66C07C2602/10A61P35/00C07D213/82C07D319/18C07D321/10C07D405/12C07D417/12
Inventor 杜彦明常锦红郭巨涛
Owner BARUCH S BLUMBERG INST
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