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Targeted contrast agents comprising hydrazide functional group

A contrast agent and functional group technology, applied in the field of targeted contrast agents containing hydrazide functional groups, can solve problems such as toxicity, instability, and slow clearance rate

Pending Publication Date: 2017-08-01
RF 医疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, problems associated with many porphyrin-based contrast agents include instability, discoloration, toxicity, and slow clearance
Several patent applications such as WO 00 / 09169 and WO 02 / 38546 discuss various non-porphyrin contrast agents that exhibit some "targeting" ability, however the reproducibility of these compounds along with the slow clearance and longevity of the compounds in the patient Related issues persist

Method used

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  • Targeted contrast agents comprising hydrazide functional group
  • Targeted contrast agents comprising hydrazide functional group
  • Targeted contrast agents comprising hydrazide functional group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Preparation of RF1311: The preparation included the steps in Scheme 1.

[0104] plan 1

[0105]

[0106] Compound 2. Under nitrogen atmosphere, ethyl indole-2-carboxylate (18.9 g, 100 mmol) was dissolved in 200 ml of ethanol; benzaldehyde (5.3 g, 50 mmol) was added, and the mixture was heated to reflux temperature. Concentrated HCl (3.7ml) was added and the reaction was left for 2 hours. After cooling, the white product was filtered off and washed well with cold ethanol. After the reaction can be TLC (CHCl 3 :hexane=1:1). The yield was 90%.

[0107] Compound 3. Compound 3 was prepared according to the modified procedure of Cresens, Erwin et al. (PCT / BE01 / 00192). 5.0 g (10.7 mmol) of compound 2 and 10 g of hydrazine monohydrate were dissolved in a mixture of 60 ml of pyridine and 30 ml of methanol. After the mixture was refluxed for 48 hours, the solvent was removed under reduced pressure. By adding H 2 O, H 2 O / methanol followed by addition of acetonitrile t...

Embodiment 2

[0111] Preparation of Rf1401: The preparation included the steps in Scheme 2.

[0112] Scenario 2

[0113]

[0114] Compound 2: Compound 1 (0.876g, 2mmol), DOTA-NHS-ester (1.0g, 2mmol, was prepared according to the procedure of Li, C.; Wong and W.-T. Tetrahedron, 2004, 60, 5595–5560 ) and DIPEA (0.284 g, 2.2 mmol) were dissolved in dry DMF (40 mL), and the resulting mixture was stirred at room temperature for 24 hours. After adding water, the solvent was removed under reduced pressure, and the resulting white powder was dissolved in in acetonitrile / H 2 O (1:1, v / v) and purified by preparative RP-HPLC. Yield: 0.59 g of white solid (0.72 mmol; 36%). 1H NMR (D 2 O)d 7.6-6.6, 14H, aromatic hydrogen and -CH; 3.7-3.0, 24H, methylene hydrogen.

[0115] RF1401: Compound 2 (0.5 mmol) was dissolved in water (30 ml), and gadolinium(III) acetate (0.5 mmol) was added slowly. During the addition, the pH was maintained at 7.4 with sodium hydroxide. After the addition, the mixture w...

Embodiment 3

[0117] RF1402 was prepared as a control compound.

[0118] Preparation of Rf1402: The preparation included the steps in Scheme 3.

[0119] Option 3

[0120]

[0121]Compound 2: DOTA (2.2 g, 5 mmol) was dissolved in 100 ml of distilled water, and the pH was adjusted to 4.8 with NaOH. The solution was cooled to 4°C and stirred. N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.92 g 10 mmol) was added followed by p-aminoaniline (7 mmol). The mixture was stirred at 4°C for 1 hour, then at room temperature for 24 hours. Purification was performed by using a preparative C18 column (200 g). The column was eluted with 10% methanol in water. The pure fractions were combined and evaporated to dryness to give the desired product as a white solid.

[0122] RF1402: Compound 2 (1.0 mmol) was dissolved in water (60 ml), and gadolinium(III) acetate (1.0 mmol) was added slowly. During the addition, the pH was maintained at 7.4 with sodium hydroxide. After the add...

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Abstract

Described herein is a contrast agent for administration to a subject. The contrast agent includes a targeting portion that includes a hydrazide functional group; a metal ion bound to a metal-complexable portion; and a linker joining the targeting portion and the metal- complexable portion of the contrast agent. The portion that is not bound to a metal ion localizes the contrast agent to necrotic tissue in the subject.

Description

[0001] References to related applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 090,519, filed December 11, 2014, and U.S. Provisional Patent Application No. 62 / 189,414, filed July 7, 2015, the entire contents of which are incorporated herein by reference. technical field [0003] The present disclosure generally relates to contrast agents and methods of their use. Background technique [0004] Medical diagnostic imaging has evolved into an important non-invasive tool for medical diagnosis. Magnetic resonance imaging ("MRI") and computed tomography ("CT") are two of the most widely used imaging methods. MRI typically relies on the relaxation properties of excited hydrogen nuclei in water. When the tissue or organ to be imaged is placed in a strong, uniform magnetic field, the spins of hydrogen protons in the tissue or organ are aligned along the axis of the magnetic field. Medical imaging techniques also inc...

Claims

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Application Information

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IPC IPC(8): A61K49/00A61K31/198A61K31/395A61K31/404A61K31/4192A61K49/04A61K49/10A61K51/04C07C243/38C07D209/42C07D249/04
CPCA61K31/395A61K49/085A61K49/10C07C243/38C07D209/42C07D249/04C07D257/02C07D403/12C07D403/14A61K49/101A61K49/108
Inventor 继东·张肯·柯里
Owner RF 医疗公司
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