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N,N-diphenylamino-modified beta-carboline indole onium salt as well as preparation method and application thereof

A technology of carboline indolium salt and diphenylamino, which is applied in chemical instruments and methods, preparations for in vivo experiments, pharmaceutical formulations, etc., and can solve the problem of inability to diagnose tumors in real time and dynamically observe tumors and normal tissues , Does not have fluorescence reversibility and other issues

Active Publication Date: 2021-11-30
NANTONG UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this type of pH probe has obvious defects. First, the process of covalent bond breaking takes a certain amount of time, and it cannot perform rapid and real-time diagnosis of tumors in spray mode; second, it does not have fluorescence reversibility, so it cannot Ability to dynamically observe tumors and normal tissues at different pH

Method used

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  • N,N-diphenylamino-modified beta-carboline indole onium salt as well as preparation method and application thereof
  • N,N-diphenylamino-modified beta-carboline indole onium salt as well as preparation method and application thereof
  • N,N-diphenylamino-modified beta-carboline indole onium salt as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: (E)-2-(2-(6-(diphenylamino)-1,9-dimethyl-9H-pyrido[3,4-b]indol-3-yl)ethylene base)-7-iodo-1,1,3-trimethyl-1H-benzo[e]indole-3-iodide salt (compound I 1 )

[0042] (1) Preparation of 6-bromo-9-methyl-9H-pyridylmethyl[3,4-b]indole-3-carboxylate (compound 2)

[0043] Firstly, compound 1 (500mg, 1.57mmol) was dissolved in anhydrous DMF, and NaH (301mg, 12.56mmol) was added under ice-bath conditions and stirred for 0.5h, then CH 3 I (1ml, 15.7mmol), after continuing to stir at room temperature for 1h, after the reaction was monitored by TLC, the reaction solution was poured into ice water, adjusted to pH 7 with 0.1mol hydrochloric acid solution, the filtrate was suction filtered, and the filter cake was dried to obtain Compound 2, yield 85%. 1 H NMR (400MHz, DMSO) δ12.21(s,1H,NH),8.84(s,1H,ArH),8.66(d,J=1.7Hz,1H,ArH),7.70(dd,J=8.7,1.9 Hz,1H,ArH),7.61(d,J=8.7Hz,1H,ArH),3.90(s,3H,OCH 3 ),2.81(s,3H,CH 3 ).

[0044] (2) Preparation of 6-(diphenylamino)-1,9-dime...

Embodiment 2

[0052] Example 2 (E)-2-(2-(6-(6-(diphenylamino)-1-methyl-9-(2-morpholinoethyl)-9H-pyrido[3,4- b]indol-3-yl)vinyl)-1,1,3-trimethyl-1H-benzo[e]indole-3-sulfonate (compound I 2 )

[0053] With reference to the preparation method of 2 in Example 1, the compound iodomethane is replaced by bromoethylmorpholine in the method, and finally the dark red product I is obtained. 2 , yield 76%. 1 H NMR(400MHz,DMSO)δ8.67(s,1H,ArH),8.23(d,J=2.1Hz,1H,ArH),8.23(m,2H,2ArH),8.06(m,2H,2ArH), 7.82 (d, J = 8.9Hz, 1H, ArH), 7.54 (m, 3H, 3ArH) 7.44 (d, J = 2.1Hz, 1H, ArH), 7.30 (m, 4H, 4ArH), 6.99 (t, J =8.2Hz, 6H, 6ArH), 4.78(dt, 2H, CH 2 ),3.54(m,4H,2CH 2 ),3.11(s,3H,CH 3 ),2.75(m,2H,CH 2 ),2.47(m,4H,2CH 2 ),2.06(s,6H,2CH 3 ),1.9(s,3H,CH 3 ).

Embodiment 3

[0054] Example 3 (E)-2-(2-(5-(6-(diphenylamino)-1,9-dimethyl-9H-pyrido[3,4-b]indol-3-yl) Thiophen-2-yl)vinyl)-1,3,3-trimethyl-3H-indole-1-bromide salt (compound I 3 )

[0055] (1) Preparation of 3-iodo-1-methyl-N,N-diphenyl-9H-pyrido[3,4-b]indol-6-amine (Compound 6)

[0056] First compound 3 (200mg, 0.508mmol), I 2 (280mg, 1.103mmol), K 3 PO 4 (186mg, 0.876mmol) was added into a sealed tube, dissolved in 2ml of acetonitrile, N 2 Protected, reacted at 110°C for 18h, after the reaction was completed, about 1.2ml of triethylamine was added to continue the reaction at 150°C for 4h, concentrated under reduced pressure, and separated by column chromatography to obtain compound 6 with a yield of 65%. 1 H NMR (400MHz, DMSO) δ8.70 (s, 1H, ArH), 8.19 (s, 1H, ArH), 7.79 (d, J = 8.9Hz, 1H, ArH), 7.42 (dd, J = 8.8, 1.9 Hz, 1H, ArH), 7.27(t, J=7.9Hz, 4H, 4ArH), 6.98(dd, J=10.7, 7.7Hz, 6H, 2CH=C, 4ArH), 4.21(s, 3H, CH 3 ),3.08(s,3H,CH 3 ).

[0057] (2) 5-(6-(diphenylamino)-1,9-dimet...

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Abstract

The invention relates to the field of biological medicines, and relates to an N,N-diphenylamino-modified beta-carboline indolium salts, a preparation method and application of the N,N-diphenylamino-modified beta-carboline indolium salt. The beta-carboline indole onium salt has a structure as shown in a general formula I, and can be activated in an acidic microenvironment of tumor tissues by utilizing an ICT principle to selectively and quickly generate pH-sensitive near-infrared fluorescence at a tumor part. According to a specific implementation method, a solution of the beta-carboline indole onium salt is sprayed or locally injected to a tumor focus part and surrounding tissues, and rapid and selective fluorescence imaging and tracing are conducted on the tumor focus tissues by using a fluorescence endoscope or a living imaging instrument. The beta-carboline indole onium salt has relatively high tumor tissue fluorescence imaging selectivity and relatively low background fluorescence interference, and can be used for accurately detecting tumors.

Description

technical field [0001] The invention relates to the field of biomedicine, and relates to a class of N,N-diphenylamino-modified β-carboline indolium salts, a preparation method and application thereof, in particular to a class of pH-sensitive N,N-diphenylamino-modified β-carboline indolium and its preparation method and application. Background technique [0002] Cancer is one of the deadliest diseases faced by human beings. According to the statistics of the World Health Organization in 2018, there were 18.1 million new cancer cases and 9.6 million cancer deaths worldwide. However, if it were possible to image tumors early in their development, this would greatly improve cancer mortality. [0003] Common clinical imaging techniques such as CT, MRI, and PET are difficult to provide accurate diagnostic guidance for tumors due to their limited spatial resolution. In contrast, fluorescence imaging technology has attracted more and more attention due to its advantages of high se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C09K11/06A61K49/00
CPCC07D471/04C09K11/06A61K49/0021C09K2211/1014C09K2211/1044C09K2211/1092C09K2211/1029C09K2211/1033
Inventor 凌勇杨宇民李鹏钱建强孟迟张延安许中原丁倩缪道鑫张雨婷
Owner NANTONG UNIVERSITY
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