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Iodine isotope labeled benzyl phenyl ether derivatives, preparation method, pharmaceutical composition and application thereof

A kind of technology of benzyl phenyl ether and derivatives, applied in the field of iodine radioisotope labelling of benzyl phenyl ether derivatives

Pending Publication Date: 2020-09-15
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, targeting PD-L1 radioligand based on small molecules may be an ideal imaging agent, which has not been reported yet.

Method used

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  • Iodine isotope labeled benzyl phenyl ether derivatives, preparation method, pharmaceutical composition and application thereof
  • Iodine isotope labeled benzyl phenyl ether derivatives, preparation method, pharmaceutical composition and application thereof
  • Iodine isotope labeled benzyl phenyl ether derivatives, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0273] Example 1: (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzyl)serine isopropyl ester

[0274]

[0275] 2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzaldehyde:

[0276] Weigh 2-hydroxy-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzaldehyde (720mg, 1.414mmol) in a 50ml single-necked bottle, dissolve it completely with 25ml DMF, add cesium carbonate (1.38 g, 4.24mmol), stirred at room temperature for 10min, added 3-chloromethylpyridine hydrochloride (348mg, 2.12mmol), raised the temperature to 76°C, and reacted for 3.5h, (TLC detection, the raw material reacted completely), added water and acetic acid Extracted three times with ethyl ester, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 830 mg of off-white solid. 1 H NMR (400MHz, DMSO-d6)δ10.09(s,1H,-CHO),8.70(s,1H,-ArH),8.53(d,J=6.2Hz,1H,-ArH),8.02(s, 1H,-ArH),7.93(m,1H,-ArH),7....

Embodiment 2

[0279]Example 2: (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzyl)serine

[0280]

[0281] Weigh (S)-N-(2-(pyridine-3-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzyl)serine isopropyl ester (186mg, 0.254mmol), dissolved in 6ml MeOH / H 2 O (5:1) mixture, stirred at room temperature, added lithium hydroxide monohydrate (43mg, 1.018mmol), reacted at room temperature for 2h, concentrated under reduced pressure, added 1.5ml of distilled water, in ice bath conditions, with glacial acetic acid The pH was adjusted to 6, and a solid was precipitated, left to stand, and filtered with suction to obtain 128 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.69(s,1H,-ArH),8.51(d,J=4.0Hz,1H,-ArH),7.94(d,J=7.8Hz,1H,-ArH),7.78(s,1H,- ArH),7.68(d,J=9.0Hz,1H,-ArH),7.51-7.45(m,1H,-ArH),7.45–7.41(m,2H,-ArH),7.41–7.32(m,5H, -ArH),6.96(s,1H,-ArH),5.30-5.20(m,4H,-2CH 2 -),3.91(s,2H,-CH 2 -),3.70-3.55(m,2H,-CH 2 -),3.15(t,J=4.9Hz,1H,-CH-).MS: [M+H] + :689.

Embodiment 3

[0282] Example 3: (S)-N-(2-(2-cyanopyridine-4-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzyl)serine Isopropyl ester

[0283]

[0284] 2-(2-cyanopyridine-4-methoxy)-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzaldehyde

[0285] Weigh 2-hydroxy-4-(2-bromo-3-phenylbenzyloxy)-5-iodobenzaldehyde (731mg, 1.44mmol) in a 50ml single-necked bottle, dissolve it completely with 8ml DMF, add potassium carbonate (597mg , 4.32mmol), after stirring at room temperature for 10min, add 3ml of DMF solution of 4-bromomethyl-2cyanopyridine (425mg, 2.16mmol), after reacting at room temperature for 12h, TLC detection, the raw material reaction is complete, add appropriate amount of water, precipitate a large amount of The white solid was suction filtered, washed with water, and dried to obtain 678 mg of white solid. 1 H NMR (500MHz, DMSO-d 6 )δ10.26(s,1H,-CHO),8.78(d,J=5.0Hz,1H,-ArH),8.22(s,1H,-ArH),8.10(s,1H,-ArH),7.88( d,J=5.1Hz,1H,-ArH),7.73(d,J=7.6Hz,1H,-ArH),7.56-7.46(m,3H,-ArH),7.46–7.3...

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Abstract

The invention discloses a class of iodine radioisotope labeled benzyl phenyl ether derivatives, a preparation method, a pharmaceutical composition and application thereof, and specifically relates toa benzyl phenyl ether derivative represented by a general formula I, a pharmaceutical salt, a stereoisomer and a preparation method thereof, a composition containing one or more radioactive compounds,and application of the radioactive compounds as PD-L1 tracers in human or animal bodies in diagnosis and treatment of diseases related to PD-1 / PD-L1 signaling pathways, such as cancer, infectious diseases and autoimmune diseases.

Description

technical field [0001] The invention discloses a class of iodine radioactive isotope labeled benzylphenyl ether derivatives, its preparation method, pharmaceutical composition and application. Specifically, it relates to benzylphenyl ether derivatives represented by general formula I, their pharmaceutically acceptable salts, their stereoisomers and their preparation methods, compositions containing one or more of these radioactive compounds, and such radioactive compounds. The compound is used as a PD-L1 tracer in humans or animals to diagnose and treat diseases related to the PD-1 / PD-L1 signaling pathway, such as cancer, infectious diseases, and autoimmune diseases. Background technique [0002] With the in-depth study of tumor immunity, it has been found that the tumor microenvironment can protect tumor cells from being recognized and killed by the body's immune system, and the immune escape of tumor cells plays a very important role in the occurrence and development of tu...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D213/84C07D405/12C07D405/14A61K31/4439A61K31/4545A61K31/4427A61K31/44A61K31/4433A61K51/04A61P35/00A61P31/04A61P31/12A61P37/02A61P5/16A61P3/10A61P5/14A61P21/04A61P1/04A61P7/06A61P13/12A61P1/16A61P25/00A61P29/00A61P19/02A61K101/02
CPCC07D401/12C07D213/84C07D405/12C07D405/14A61K51/0455A61P35/00A61P31/04A61P31/12A61P37/02A61P5/16A61P3/10A61P5/14A61P21/04A61P1/04A61P7/06A61P13/12A61P1/16A61P25/00A61P29/00A61P19/02A61K2121/00
Inventor 冯志强杨阳
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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