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Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents

A compound and pharmaceutical technology, applied in the field of functionalized derivatives of Evans blue dye, can solve problems such as increasing insulin

Active Publication Date: 2020-08-14
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The peptide hormone GLP-1-(7-37) is produced by selective cleavage of the proglucagon molecule and increases insulin secretion in pancreatic cells, but is degraded by ubiquitous enzymes, Its half-life is only 1.5–2 minutes

Method used

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  • Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents
  • Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents
  • Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0256] Embodiment 1: Evans blue amine (EB-NH 2 ) preparation

[0257] To a 100ml round bottom flask containing 2-toluidine (4.3g) and dichloromethane (40ml) was added di-tert-butyl dicarbonate (4.4g). The mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was purified by silica gel chromatography to afford 3.2 g of N-Boc-2-benzylidine. LC-MS: [MH] + = 313.4135 (m / z), Calculated: 312.1838.

[0258]

[0259] N-Boc-2-Tolidine (0.46g, 1.47mmol) was dissolved in acetonitrile (10ml) in a glass vial, cooled to 0°C, then hydrochloric acid (0.3M, 15ml) was added. Cold sodium nitrite solution (0.31 g in 5 ml water) was added dropwise and stirred for 20 min, the solution turned bright yellow. This solution was added dropwise at 0°C to another solution containing 1-amino-8-naphthalene-2,4-disulfonic acid monosodium salt (0.59g) and sodium bicarbonate (0.49g) in water (20ml) in a glass vial. The reaction was deemed complete by LC / MS, ...

Embodiment 2

[0263] Embodiment 2: the synthesis of EB-LYS-BOC

[0264]

[0265] To a solution of Boc-Lys-Fmoc (3.6 equiv) in anhydrous N,N-dimethylformamide (DMF) (2-3 mL) under argon was added (1-[bis(dimethylamino) Methyl]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (HATU, 4.2 equivalents). The solution was stirred at room temperature (RT) for 10 minutes. Then 10 equivalents of diisopropylethylamine (DIPEA) was added, followed by EB-NH in 5-7 mL of DMF 2 . The reaction was stirred overnight at room temperature. Monitoring of EB-NH Using Analytical HPLC System 1 2 Conversion to EBs conjugated to protected Fmoc-Lys-Boc. EB-NH 2 The retention time was 7.7 minutes for the conjugated EB-protected Lys and 11 minutes for the conjugated EB-protected Lys. After conversion was complete, 20% piperidine (v / v) was added and the reaction was stirred for an additional 1 hour. DMF was removed with a high vacuum oil pump and the reactants were redissolved in methanol / HO 2 ...

Embodiment 3

[0266] Example 3: Synthesis of NOTA-EB-LYS-BOC

[0267]

[0268] The reaction between EB-Lys-Boc and NOTA-bis(t-Bu ester) was performed similarly to the conditions described above. Analytical HPLC system 2 confirmed >90% purity, r.t 29.3 min, mass 1167 [MH] - .

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Abstract

The present invention is directed to a compound of Formula III or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of the an ester or amide or a solvate of the an esteramide or salt,wherein the definitions of R1-R12 and L1-L4 are provided in the disclosure, R13 is a chelating group comprising 177Lu, and wherein R14 is a peptide. The compounds of Formula I may be covalently bonded to a peptide via a linker to provide a compound of Formula III and thereby extend the half-life of the therapeutic compound. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use in the diagnosis or treatment of diseases.

Description

technical field [0001] The present invention relates to functionalized derivatives of Evans Blue dye, and more particularly to functionalized derivatives of Evans Blue dye for use as radiotherapeutic and imaging agents. Background technique [0002] The effectiveness of a drug depends largely on pharmacokinetics. In particular, compounds for pharmaceutical use must have a sufficient half-life to exert the desired effect on the patient. Various approaches have been used to increase the half-life of pharmaceutical compounds in vivo. One approach to increasing half-life is to decrease the rate at which a drug is cleared from the body, which can be achieved by inhibiting the clearance mechanism, by modifying the drug directly or by adding other agents that act on the clearance pathway. Reduced clearance is especially desirable for protein drugs because they are highly susceptible to degradation by proteases. [0003] Since the kidney typically filters out molecules below 60 k...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D307/60C07D257/02A61K31/4015A61K31/395
CPCC07D403/12A61K31/395A61K31/4015C07D403/14C07D417/14A61K45/06A61K2300/00A61P35/04A61K51/0482A61K51/0497A61K51/082C07B59/002C07B2200/05C07D207/452
Inventor 陈小元奥里特·雅各布森·韦斯
Owner UNITED STATES OF AMERICA
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