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Long circulation iron chelator with pH response characteristic

A technology of solvents and compounds, which is applied in the field of chemically modified polycondensates, can solve the problems of increasing dosage, prolonging the time of medication, and obvious adverse reactions, and achieve the effects of improving drug efficacy, extending half-life, and improving safety

Active Publication Date: 2017-09-08
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But it has obvious defects: 1. Desferrioxamine in the blood will be rapidly degraded by enzymes in the body, and its half-life in the body is less than 30 minutes, resulting in poor drug efficacy, and it is necessary to increase the dosage or prolong the medication time; 2. It is toxic , can cause many adverse reactions, such as hypotension and tachycardia (see Yu Tianji, Desferrioxamine—New Toxicity of Old Drugs, Foreign Medicine: Pharmacy, 1991.P249,), especially at high doses, its Adverse reactions are particularly obvious
In order to take into account the efficacy and safety, the current usual treatment method is low-dose and long-term intravenous injection to maintain the concentration in the body to achieve a certain effect, but this treatment method is very inconvenient and the patient's compliance is poor

Method used

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  • Long circulation iron chelator with pH response characteristic
  • Long circulation iron chelator with pH response characteristic
  • Long circulation iron chelator with pH response characteristic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1 gram of polyethylene glycol monomethyl ether (molecular weight 1kDa) was dissolved in 10 milliliters of dichloromethane solution, added 0.4 g of p-formylbenzoic acid, 0.3 g of DMAP and 1.3 g of DCC, and reacted for 36 hours at 5° C. Silica gel column purification, to obtain the intermediate product MPEG 1k -Ph-CHO.

[0040] Weigh 0.5g intermediate product MPEG 1k -Ph-CHO was dissolved in 20 ml of methanol, 3 g of deferoxamine methanesulfonate and 2.6 ml of triethylamine were added, reacted at 60 ° C for 12 hours, and purified by silica gel column to obtain the final product MPEG 1k -Ph-DFO.

[0041] H NMR spectrum: 40mg sample dissolved in 1ml D 2 In O, at 25°C, the test results are as follows figure 2 shown.

[0042] The characteristic peaks are assigned as follows: 8.2 and 8.07ppm are H in the benzene ring; 8.1ppm are H in the CH=N bond; 3.6 and 3.3ppm correspond to methoxy and methylene in polyethylene glycol monomethyl ether, respectively. Hydrogen; 3.5ppm ...

Embodiment 2

[0045] 1 gram of polyethylene glycol monomethyl ether (molecular weight 2kDa) was dissolved in 10 milliliters of dichloromethane solution, 0.2 g p-formylbenzoic acid, 0.15 g DMAP and 0.63 g DCC were added, and after reacting for 72 hours at -5°C, Purified by silica gel column to obtain the intermediate product MPEG 2k -Ph-CHO.

[0046] Weigh 0.5g of the intermediate product MPEG2k-Ph-CHO and dissolve it in 20ml of methanol, add 1.5g of deferoxamine methanesulfonate and 1.3ml of triethylamine, react at 60°C for 12 hours, and purify through a silica gel column to obtain the final Product MPEG 2k -Ph-DFO.

Embodiment 3

[0048] 1 gram of polyethylene glycol monomethyl ether (molecular weight 5kDa) was dissolved in 10 milliliters of dichloromethane solution, added 0.08g p-formylbenzoic acid, 0.06g DMAP and 0.25g DCC, reacted under ice bath for 40 hours, after Silica gel column purification, to obtain the intermediate product MPEG 5k -Ph-CHO.

[0049] Weigh 0.5g of the intermediate product MPEG5k-Ph-CHO and dissolve it in 20ml of methanol, add 0.6g of deferoxamine methanesulfonate and 0.5ml of triethylamine, react at 60°C for 12 hours, and purify through a silica gel column to obtain the final Product MPEG 5k -Ph-DFO.

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Abstract

The invention discloses a long circulation iron chelator with a pH response characteristic. The long circulation iron chelator is formed by connecting polyethylene glycol monomethyl ether with good biocompatibility and deferoxamine through a pH sensitive chemical bond. The invention further discloses a preparation method of the long circulation iron chelator, and the preparation method comprises the steps of connecting polyethylene glycol monomethyl ether with carboxybenzaldehyde through an esterification reaction, and enabling an intermediate product to react with the deferoxamine through a schiff base to prepare the long circulation iron chelator with the pH response characteristic. Compared with the deferoxamine, the disclosed iron chelator has the characteristics of long effect and response to an acid micro-environment of a lesion location, and has a potential application value in the treatment of iron overload related diseases.

Description

technical field [0001] The invention belongs to the field of chemically modified condensation polymers, and in particular relates to deferoxamine grafted polyethylene glycol with pH response, and also relates to its application as an iron ion chelating agent. Background technique [0002] Iron ion overload is associated with many clinical diseases, such as thalassemia, stroke, Alzheimer's, Parkinson's disease and other neurodegenerative diseases. [0003] Desferrioxamine is an iron ion chelator commonly used clinically, and has therapeutic effects on diseases related to iron ion overload. But it has obvious defects: 1. Desferrioxamine in the blood will be rapidly degraded by enzymes in the body, and its half-life in the body is less than 30 minutes, resulting in poor drug efficacy, and it is necessary to increase the dosage or prolong the medication time; 2. It is toxic , can cause many adverse reactions, such as hypotension and tachycardia (see Yu Tianji, Desferrioxamine—N...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/333C08G65/332A61P3/12A61K31/555
CPCC08G65/3326C08G65/33396
Inventor 田猛李浩马潞游潮陈茂君
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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