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Benzoxadiazole compound and preparation method and medical use thereof

A technology of benzoxadiazoles and compounds, applied in the field of benzoxadiazoles, pharmaceutical compositions for tumor immunotherapy

Active Publication Date: 2019-05-21
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, small molecule inhibitors of PD-1 / PD-L1 are still in the early stage of research and development

Method used

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  • Benzoxadiazole compound and preparation method and medical use thereof
  • Benzoxadiazole compound and preparation method and medical use thereof
  • Benzoxadiazole compound and preparation method and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzo[c ][1,2,5]oxadiazol-4-yl)methyl)-D-serine (compound 1)

[0110]

[0111] synthetic route:

[0112]

[0113] Synthesis of Compound I-2

[0114] Dissolve compound M-2 (1.8g) in anhydrous acetone (30mL), add anhydrous sodium bicarbonate (1.3g) and tetrabutylammonium iodide (TBAI, 300mg), and slowly add I-1 (2g ), protected by argon, and heated in an oil bath at 70°C. After reacting for about 6 hours, the heating was stopped, the solvent was evaporated under reduced pressure, diluted with ethyl acetate (25 mL), washed with water (10 mL x3) and saturated brine (10 mL x2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate=3:1) to obtain compound I-2 (2.14 g) as a light yellow solid.

[0115] Synthesis of Compound I-3

[0116] Compound I-2 (2.33 g) was dissolv...

Embodiment 2

[0128] N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy) Benzo[c][1,2,5]oxadiazol-4-yl)methyl)amino)ethyl)acetamide (compound 2)

[0129]

[0130] Referring to the method of Example 1, the D-serine ethyl ester hydrochloride in Example 1 was replaced by N-acetylethylenediamine to obtain compound 2: 1 H NMR (300MHz, CDCl 3 )δ7.73(s,1H),7.71–7.60(m,2H),7.54(t,J=7.7Hz,1H),7.40(m,J=13.3,6.7Hz,4H),7.29(m,4H ),6.58(s,1H),6.28(s,1H),5.38(s,2H),5.21(s,2H),4.09(s,2H),3.34(dd,J=10.8,5.3Hz,2H) ,2.74(t,J=5.6Hz,2H),2.28(s,3H),1.95(s,3H).HRMS(ESI):m / z 562.24496[M+H] + .

Embodiment 3

[0132] N-((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzo[c ][1,2,5]oxadiazol-4-yl)methyl)glycine (Compound 3)

[0133]

[0134] Referring to the method of Example 1, the D-serine ethyl ester hydrochloride in Example 1 was replaced with glycine methyl ester hydrochloride to obtain compound 3: 1 H NMR (300MHz, CD 3 OD)δ7.95–7.83(m,2H),7.75–7.54(m,3H),7.50–7.21(m,7H),6.96(s,1H),5.44(s,2H),5.40(s,2H ),4.05(s,2H),3.18(s,2H),2.27(s,3H).MS(ESI):m / z 533.3[M-H] + .

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PUM

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Abstract

The invention discloses a benzoxadiazole compound and a preparation method and medical use thereof. The benzoxadiazole compound has the general structure shown in formula (I). The compound or pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates of the benzoxadiazole compound have an obvious inhibiting effect on PD-1 / PD-L1 protein-protein interaction, so that the benzoxadiazole compound shown in the description can be applied to the preparation of an inhibitor with a PD-1 / PD-L1 inhibitory activity and the immunotherapy of tumors as an immunocheckpoint inhibitor.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a benzoxadiazole compound having PD-1 / PD-L1 inhibitory activity. Medical use of inhibitor and pharmaceutical composition for tumor immunotherapy. Background technique [0002] Programmed death receptor 1 (PD-1) is mainly expressed on the surface of T cells and is an important factor in the immune checkpoint pathway of the body. The PD-1 ligand highly expressed on the surface of tumor cells, that is, programmed death ligand 1 (PD-L1), when it binds to PD-1 on the surface of T cells, ITIM (Tyr223) and ITSM ( Tyr248) tyrosine motifs were phosphorylated, respectively, and subsequently recruited protein tyrosine phosphatases SHP-2 and SHP-1, which dephosphorylated signaling intermediates (such as CD3ζ and PLCγ1, etc.), resulting in T cell receptor ( The down-regulation of TCR) signal enables tumor cells to escape the immune surveillance of the body (Immunity 2016,44(5):955-972)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/12C07D413/12C07D413/14A61K31/4245A61K31/4439A61K31/4545A61K45/06A61P35/00A61P35/02
Inventor 孙宏斌刘鎏姚智颖
Owner CHINA PHARM UNIV