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Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer

A technology of compounds, radionuclides, applied in the field of functionalized derivatives of Evans blue dye

Pending Publication Date: 2020-10-02
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, to date, no PSMA small molecule has been approved by the US Food and Drug Administration as a diagnostic / therapeutic agent

Method used

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  • Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer
  • Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer
  • Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents for targeting prostate cancer

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0095] One aspect of the present invention includes a chemical conjugate of Evans blue dye having a compound of formula I shown below, or a pharmaceutically acceptable ester, amide, solvate or salt thereof, or a salt of such an ester or amide or solvates of such ester amides or salts:

[0096]

[0097] In formula I, the substituent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 independently selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Haloalkoxy. R 12 for hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl. R 13is a chelating group. R 14 is a group capable of binding prostate-specific membrane antigen (PSMA).

[0098] Formula I may also include a linking group L 1 , which is -(CH 2 ) m -, wherein m is an integer from 0 to 12; linking group L 2 Yes-(CH 2 ) n -, wherein n is an integer from 0 to 12; and the linking group L 3 Yes-(CH 2 ) p -, wherein p is...

Embodiment 1

[0181] Embodiment 1: the synthesis of DOTA-maleimide-EB (DMEB)

[0182] Step 1-2: Synthesis of benzidine-Lys-Boc

[0183]

[0184] To a 100 mL round bottom flask containing 1.1 g of Boc-lysine-Fmoc amino acid (1 eq) and anhydrous N,N-dimethylformamide (DMF) (10 mL) was added HATU (0.94 g ,1.05eq). The mixture was stirred at room temperature (RT) for 10-15 minutes. Then, diisopropylethylamine (DIPEA) (4 mL, 10 eq) was added, followed by a solution of benzidine (0.75 g, 1.5 eq) in 10 mL of DMF. The reaction mixture was stirred overnight. Conversion to the target product was evaluated by analytical HPLC using System 1 (retention time 32.3 minutes). Solvent was removed by rotary evaporator using an oil vacuum pump. The remaining oil was redissolved in 5-10 mL of DMF, followed by the addition of 20% piperidine (v / v). The mixture was stirred at room temperature for 15-20 and assessed for deprotection of Fmoc by injection into analytical HPLC system 1 (retention time 18.7 mi...

Embodiment 2

[0198] Example 2: Alternative Synthesis of DOTA-Maleimide-EB (DMEB)

[0199] Step 1: Evansblue amine (EB-NH 2 ) preparation

[0200] 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 obtain 3.2 g of N-Boc-2-benzylidine. LC-MS: [MH]+ = 313.4135 (m / z), Calculated: 312.1838.

[0201]

[0202] In a glass vial, N-Boc-2-toluidine (0.46g, 1.47mmol) was dissolved in acetonitrile (10ml), cooled to 0°C, then hydrochloric acid (0.3M, 15ml) was added. Cold sodium nitrite solution (0.31 g in 5 ml of water) was added dropwise and stirred for 20 minutes, the solution turned bright yellow. At 0°C, this solution was added dropwise to a solution of 1-amino-8-naphthol-2,4-disulfonic acid monosodium salt (0.59 g) and sodium bicarbonate (0.49 g) in water (20 ml). i...

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Abstract

A compound of Formula (I) or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt. Definitions of R1-R13 and L1-L4 are provided in the disclosure, and R14 is a group capable of binding to prostate-specific membrane antigen (PSMA).

Description

[0001] Citations to related applications [0002] This application claims priority to and benefit of U.S. Provisional Application No. 62 / 633,648, filed February 22, 2018, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to functionalized derivatives of Evans Blue dye, and more particularly, to functionalized derivatives of Evans Blue dye useful as radiotherapy and imaging agents for targeting prostate cancer . Background technique [0004] Prostate cancer is the most common malignancy in men worldwide. Prostate-specific membrane antigen (PSMA) is a surface molecule demonstrated to be specifically expressed by prostate tumor cells. PSMA expression levels correlate with disease stage and hormone-refractory cancers. Although most PSMA expression appears to be restricted to prostate cancer, low-level expression can also be detected in the brain, kidney, salivary glands, and small intestine. This antigen has als...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/395A61K31/4015A61K51/08C07D207/444C07D207/452
CPCA61K51/0402A61K51/0497A61K45/06C07D403/12A61P35/00C09B29/007C09B29/30A61P13/08A61K31/4025C07D207/40A61K31/4015A61K51/08A61K51/044A61K51/0482A61K47/547A61K49/0052
Inventor 陈小元欧里特·雅各布森·韦斯
Owner UNITED STATES OF AMERICA
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