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Near-infrared fluorescent probe for specifically targeting tumor as well as synthesis method and application of near-infrared fluorescent probe

A technology of fluorescent probe and synthesis method, applied in the field of specific molecular targeted diagnostic reagents, which can solve the problems of false positives of ICG, unfavorable imaging of liver and intestinal tumors, etc.

Active Publication Date: 2022-03-29
NANJING NUOYUAN MEDICAL DEVICES CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Indocyanine Green (ICG) is a near-infrared fluorescent dye approved by the FDA. It can bind to plasma proteins and accumulate to the tumor site through the EPR effect. Generally, it is administered intravenously the day before surgery, and after one day of metabolism, it is administered the next day. During the operation, the liver and intestines in the body are basically cleared, so that it will not interfere with the operation. The problem is that it needs to be administered one day in advance, and the liver and intestines are metabolized, which is not conducive to imaging of liver and intestinal tumors, and ICG is prone to false positives.

Method used

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  • Near-infrared fluorescent probe for specifically targeting tumor as well as synthesis method and application of near-infrared fluorescent probe
  • Near-infrared fluorescent probe for specifically targeting tumor as well as synthesis method and application of near-infrared fluorescent probe
  • Near-infrared fluorescent probe for specifically targeting tumor as well as synthesis method and application of near-infrared fluorescent probe

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the synthesis of YQ-H-01

[0034]

[0035]

[0036] Lapatinib (5mg, 1.0eq), ICG-02 (12mg, 1.5eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea Fluorophosphate (HATU, 13mg, 4.0eq), triethylamine (6ul, 5.0eq), reacted at room temperature in the dark for 3 hours, and monitored the reaction by HPLC. After the reaction was complete, it was purified by preparative liquid phase, and the target fraction was freeze-dried to obtain Green solid YQ-H-01 (5 mg, Y=38.9%), confirmed by mass spectrometry and NMR spectroscopy, m / z=, 1 H NMR (300 MHz, DMSO) δ 8.88 (dd, J = 15.1,10.5 Hz, 2H), 8.66 (t, J = 12.4 Hz, 2H), 8.24 (dd, J = 11.1, 6.4 Hz, 1H), 8.01 (t, J = 2.8 Hz, 1H), 7.85-7.66 (m, 4H), 7.60-7.45 (m, 3H), 7.42-7.16 (m,7H), 6.52 (dt, J = 24.9, 7.5 Hz, 3H), 5.34 (s, 2H), 4.64 (s, 2H), 4.26 (d, J = 7.2 Hz, 4H), 3.39 (t, J = 8.0 Hz, 2H), 3.17 (s, 2H), 3.04 (d, J = 9.4 Hz,4H), 2.73-2.59 (m, 8H), 2.55 (s, 3H), 2.07-1.88 (m, 4H), 1.78-1.65 (m, 2H),...

Embodiment 2

[0037] Embodiment 2: the synthesis of YQ-H-03

[0038]

[0039]

[0040] Lapatinib (10mg, 1.0eq), 6-Boc-aminocaproic acid (8 mg, 2eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (HATU, 13mg, 2.0eq), triethylamine (7.2ul, 3.0eq), react at room temperature for 1 hour, TLC monitors the reaction, after the reaction is complete, drop the reaction solution into water, and then Ethyl acetate was extracted, and the combined organic layer was concentrated and added trifluoroacetic acid to remove Boc. The reaction was also monitored by TLC. After the reaction was complete, the trifluoroacetic acid was evaporated and purified to obtain lapatinib linked to 6-aminocaproic acid. Subsequent synthesis of the reference compound YQ-H-01 yielded the target compound YQ-H-03, a green solid, whose structure was confirmed by mass spectrometry and nuclear magnetic proton spectroscopy, m / z=, 1H NMR (300 MHz, DMSO) δ 8.88 (dd, J = 15.1,10.5 Hz, 2H), 8.66 (t, J = 12.4 H...

Embodiment 3

[0041] Embodiment 3: the synthesis of YQ-H-04

[0042]

[0043] The synthesis method refers to YQ-H-03, the structure is confirmed by mass spectrometry and NMR spectrum, m / z=, 1 H NMR (300 MHz, DMSO) δ 8.96 (dd, J = 8.0, 4.8 Hz, 2H), 8.66 (d, J = 14.0 Hz, 2H), 8.36 (d, J = 8.9 Hz, 1H), 8.01 -7.88 (m, 3H), 7.75 (d, J = 1.2 Hz, 2H), 7.65 (ddd, J =9.6, 8.6, 1.9 Hz, 3H), 7.53-7.46 (m, 1H), 7.45-7.30 (m, 5H ), 7.25-7.14 (m,2H), 6.64-6.43 (m, 3H), 5.32 (s, 2H), 4.72 (d, J = 23.4 Hz, 2H), 4.40-4.23(m, 4H), 3.61- 3.53 (m, 2H), 3.51-3.41 (m, 12H), 3.41-3.30 (m, 4H), 3.19-3.12(m, 2H), 3.03 (d, J = 4.6 Hz, 2H), 2.97 (td, J = 6.6, 3.9 Hz, 2H), 2.76 (dd, J = 11.9, 5.0 Hz, 2H), 2.73-2.59 (m, 8H), 2.55 (s, 3H), 2.42-2.31 (m, 2H), 2.10 -1.91 (m, 4H), 1.80-1.71 (m, 2H), 1.65 (d, J = 2.0 Hz, 12H).

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Abstract

The invention discloses a near-infrared fluorescent probe for specifically targeting tumors as well as a synthesis method and application thereof, the near-infrared fluorescent probe is a compound shown in the following formula I or pharmaceutically acceptable salt thereof, wherein X is a connecting molecule selected from null, PEGn and glycine (Gm), n is equal to 0-10, m is equal to 0-10, one end of the connecting molecule is amino, and the other end of the connecting molecule is carboxyl; y is a dye molecule having a fluorescence excitation and emission spectrum in a near infrared (NIR) range, and the compound as shown in the formula I or the pharmaceutically acceptable salt thereof can maintain or enhance the fluorescence of the dye molecule Y. The near-infrared fluorescent probe disclosed by the invention can be quickly cleared in normal tissues and detained in tumor parts for a long time, so that the effect of in-vivo diagnosis can be achieved, and the near-infrared fluorescent probe has a certain clinical application prospect and is applied to clinical intraoperative navigation.

Description

technical field [0001] The invention belongs to the technical field of specific molecular targeting diagnostic reagents, and in particular relates to a diagnostic reagent complex composed of a near-infrared fluorescent dye, a linker molecule and a small molecule inhibitor lapatinib. Background technique [0002] At present, cancer is one of the chief culprits that seriously endanger the health of residents in my country except cardiovascular diseases, and seriously endanger human health. The clinical treatment of tumors mainly includes surgical resection, chemotherapy drugs, radiotherapy drugs and so on. Among them, surgical resection is one of the best treatments for all solid tumors. Effective surgical resection can greatly prolong the survival period of patients. In recent years, the emergence of various advanced instruments and equipment, such as MRI, ultrasound imaging, Spect / CT imaging, etc., can accurately locate tumors, find out the location of the lesion, and then ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07K5/083C07K7/06C09K11/06G01N21/64
CPCC07D405/14C09K11/06C07K5/0806C07K7/06G01N21/6486C09K2211/1029C09K2211/1044C09K2211/1088C09K2211/1007A61K49/0032A61K49/0052C09B23/0066C09B23/06
Inventor 蔡惠明顾月清李昌盛
Owner NANJING NUOYUAN MEDICAL DEVICES CO LTD
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