Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof

A technology of nitrophenyl ethers and compounds, which is applied in the field of nitrophenyl ether compounds, their preparation, pharmaceutical composition and application, and can solve problems such as difficulty in preparation and purification, side effects, and inability to be administered orally

Active Publication Date: 2020-05-22
CHINA PHARM UNIV +1
View PDF4 Cites 3 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof
  • Nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof
  • Nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof

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).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses nitrophenyl ether compounds, and preparation methods, pharmaceutical compositions and application thereof, belonging to the field of medicines. The invention particularly relates to the nitrophenyl ether compounds with structural characteristics of a general formula (I) which is described in the specification, stereoisomers, metabolites, metabolic precursors, prodrugs, solvates, crystals or pharmaceutically acceptable salts of the nitrophenyl ether compounds, the preparation methods of the nitrophenyl ether compounds, and application of the nitrophenyl ether compounds and the stereoisomers, the metabolites, the metabolic precursors, the prodrugs, the solvates, the crystals and the pharmaceutically acceptable salts thereof as PD-1 / PD-L1 inhibitors. Pharmacological experiment results show that the compounds disclosed by the invention have remarkable inhibition activity on PD-1 / PD-L1 protein-protein interaction and can effectively inhibit PD-1 / PD-L1 mediated tumorimmune escape, so the compounds can be used for preparing inhibitors with the activity of inhibiting PD-1 / PD-L1 and can be used as immune checkpoint inhibitors for immunotherapy of tumors.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com