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Nitrophenyl ether compound, its preparation method, pharmaceutical composition and application

A technology for nitrophenyl ether and amine compounds, applied in the fields of nitrophenyl ether compounds, their preparation, pharmaceutical compositions and uses, can solve the problems of excessive activation of T cells, high price, poor compliance and the like, and achieve significant inhibition Activity, growth inhibition, and expression-reducing effects

Active Publication Date: 2021-10-29
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, PD-1 / PD-L1 monoclonal antibody drugs also have obvious shortcomings, such as easy to cause excessive activation of T cells, causing immune-related side effects, and cannot be administered orally, poor compliance, and difficult to prepare and purify, resulting in high price. Expensive etc.

Method used

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  • Nitrophenyl ether compound, its preparation method, pharmaceutical composition and application
  • Nitrophenyl ether compound, its preparation method, pharmaceutical composition and application
  • Nitrophenyl ether compound, its preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Synthesis of (3-nitro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-L-serine (1)

[0079]

[0080] Synthesis of ethyl 2-methyl-3-bromobenzoate (1A)

[0081] Dissolve 2-methyl-3-bromobenzoic acid (10.0g, 46.5mmol) in ethanol (50mL), slowly drop into 20mL SOCl under ice-cooling 2 , After dropping, place it in an oil bath and heat at 70°C and stir for 2 hours. Cool, add 200 mL of water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous magnesium sulfate, filter with suction, and concentrate under reduced pressure to obtain 1A, which is directly put into the next reaction.

[0082] Synthesis of [1,1'-biphenyl]-2-methyl-3-carboxylic acid ethyl ester (1B)

[0083] 1A (4.0 g, 16.5 mmol), phenylboronic acid (3.0 g, 24.7 mmol) and potassium acetate (4.8 g, 49.4 mmol) were added to 30 mL of DMF and 8 mL of water, and Pd(dppf)Cl was added 2 (1.2g, 1.7mmol), reacted at 90°C for 12h under nitrogen protection, suction filt...

Embodiment 2

[0094] Synthesis of (3-nitro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-L-threonine (2)

[0095]

[0096] Referring to the method of Example 1, the L-serine methyl ester hydrochloride in Example 1 was replaced with L-threonine methyl ester hydrochloride to obtain a white solid with a yield of 51%. MS(EI) m / z 449.1[M-H] - ; 1 H NMR (300MHz, DMSO) δ8.05 (d, J = 2.0Hz, 1H), 7.83-7.76 (m, 1H), 7.62-7.54 (m, 1H), 7.47 (dd, J = 14.8, 8.0Hz, 4H), 7.39(d, J=7.2Hz, 1H), 7.32-7.26(m, 3H), 7.20(d, J=7.8Hz, 1H), 5.35(d, J=7.9Hz, 2H), 4.00- 3.93(m,2H),3.16(d,J=5.6Hz,1H),2.20(s,3H),1.16(d,J=6.3Hz,2H).

Embodiment 3

[0098] Synthesis of (3-nitro-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-L-proline (3)

[0099]

[0100] Referring to the method of Example 1, the L-serine methyl ester hydrochloride in Example 1 was replaced with L-provinyl methyl ester hydrochloride to obtain a white solid with a yield of 50%. MS(EI) m / z 445.1[M-H] - ; 1 H NMR (300MHz, DMSO) δ8.06(s, 1H), 7.82(d, J=7.2Hz, 1H), 7.62(d, J=8.9Hz, 1H), 7.48(dd, J=16.4, 7.8Hz ,3H),7.38(t,J=7.2Hz,1H),7.30(dd,J=6.8,4.6Hz,3H),7.22(d,J=6.8Hz,1H),5.37(s,2H),4.31 (d,J=13.3Hz,1H),4.10(d,J=12.7Hz,1H),3.87(s,1H),3.27(s,2H),2.93(d,J=8.6Hz,1H),2.21 (s,3H),1.93(s,2H),1.82(s,1H).

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Abstract

Nitrophenyl ether compound, its preparation method, pharmaceutical composition and use. The invention belongs to the field of medicines, in particular to a nitrophenyl ether compound having the structural characteristics of general formula (I), its stereoisomers, metabolites, metabolic precursors, prodrugs, solvates, crystals or pharmaceutically Acceptable salts, methods for their preparation, and their use as PD‑1 / PD‑L1 inhibitors. The results of pharmacological experiments show that the compound of the present invention has significant inhibitory activity on PD-1 / PD-L1 protein-protein interaction, and can effectively inhibit PD-1 / PD-L1-mediated tumor immune escape, so it can be used to prepare It has an inhibitor of PD-1 / PD-L1 activity, and can be used as an immune checkpoint inhibitor for tumor immunotherapy.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a class of nitrophenyl ether compounds or their stereoisomers, pharmaceutically acceptable salts, crystals, and solvents as PD-1 / PD-L1 protein-protein interaction inhibitors Compounds or prodrugs, their preparation methods, pharmaceutical compositions containing these compounds, and uses of these compounds or compositions in the treatment of diseases related to PD-1 / PD-L1-mediated immunosuppression, such as cancer. Background technique [0002] Immune escape is a fundamental feature of malignant tumors. Under normal physiological conditions, the body's immune system can recognize foreign molecules and clear them in time. But for cancer patients, due to the low immunity of the body and the special biological characteristics of tumor cells, tumor cells can escape the recognition and killing of the immune system through various mechanisms, and finally survive and develop in th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/58C07C213/02C07C227/18C07C229/10C07C229/22C07C231/12C07C233/36C07C253/30C07C255/54C07C323/58C07C319/20C07D207/16C07D211/60C07D213/30C07D213/84C07D307/52C07D401/12C07K5/078A61P35/00A61P35/02A61K38/05A61K31/4545A61K31/44A61K31/4406A61K31/445A61K31/277A61K31/401A61K31/137A61K31/198A61K31/341A61K31/197A61K31/165
CPCA61P35/00A61P35/02C07C217/58C07C229/10C07C229/22C07C233/36C07C255/54C07C323/58C07D207/16C07D211/60C07D213/30C07D213/84C07D307/52C07D401/12C07K5/06139
Inventor 赖宜生欧阳宜强鲁俊峰赵磊金双龙岳露徐强郭文洁高健
Owner CHINA PHARM UNIV
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