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Preparation and application of monodisperse polyethylene glycol monomethyl ether modified propofol prodrug

A technology of polyethylene glycol monomethyl ether and propofol, applied in the field of preparation and application of propofol prodrugs, can solve the problems of aggravating hypotension, transient apnea, short shelf life, injection pain and the like

Active Publication Date: 2018-06-15
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Propofol (2,6-diisopropylphenol) is a general anesthetic for intravenous injection of alkylphenols, and has been widely accepted as a short-acting intravenous anesthetic. short, the patient has no side effects such as coughing and hiccups. In addition to its many advantages as an anesthetic, propofol also has a series of other valuable applications. It is reported that it also has antiemetic, anti-anxiety, neuroprotection, Itching, pain relief, inhibition of platelet aggregation, inhibition of inducible NO production, etc., but it is highly fat-soluble and almost insoluble in water. Propofol is clinically prepared as an oil-in-water fat oil emulsion, but the preparation The disadvantage is that the shelf life is short, and it is sensitive to bacterial and fungal contamination, which will cause injection pain, and the lipid components will aggravate the hypotension and transient apnea caused by propofol, and long-term use may lead to hyperlipidemia, etc. These characteristics are very This limits its clinical application to a large extent

Method used

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  • Preparation and application of monodisperse polyethylene glycol monomethyl ether modified propofol prodrug
  • Preparation and application of monodisperse polyethylene glycol monomethyl ether modified propofol prodrug
  • Preparation and application of monodisperse polyethylene glycol monomethyl ether modified propofol prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0056] Embodiment 3 Solubility Measurement Experiment

[0057] The solubility of compounds 1a-1f and 2a-2f in PBS buffer (pH=7.4) was determined by UV spectrophotometry. First, measure the UV absorbance of solutions with different concentrations of the compound at a wavelength of 257 nm, draw a standard curve to obtain a regression curve equation, then prepare a saturated solution of the compound, centrifuge the saturated solution and dilute the supernatant to a certain concentration, and then measure its concentration in The wavelength is the absorbance value at 257nm, which is brought into the standard curve equation to obtain the diluted concentration of the saturated solution of the compound, and then multiplied by the dilution factor to obtain the solubility of the compound in PBS buffer (pH=7.4). The solubility measurement results are shown in Table 1. The longer the chain of monodisperse polyethylene glycol monomethyl ether, the better the solubility of propofol prodrug...

Embodiment 4

[0061] Example 4 Cell Viability Experiment

[0062] (1) Preparation of solution

[0063] Preparation of DMEM high glucose medium: buy DMEM high glucose medium, 500mL per bottle, add 10% fetal bovine serum and 1% penicillin-streptomycin solution, that is, add 50mL fetal bovine serum and 5mL to each bottle of medium of penicillin-streptomycin solution, the preparation of the medium was carried out in an ultra-clean workbench, and the prepared DMEM high-glucose medium was placed in a refrigerator at 4°C for storage.

[0064] Preparation of PBS buffer: In a 1000 mL conical flask, weigh 8 g of sodium chloride, 0.2 g of potassium chloride, 2.9 g of disodium hydrogen phosphate dodecahydrate, and 0.2 g of potassium dihydrogen phosphate, add 800 mL of pure water and stir to dissolve Then, the volume was adjusted to 1000 mL, and then stored in the refrigerator at 4°C after autoclaving.

[0065] Preparation of MTT solution: Weigh 0.5 g of MTT dry powder, dissolve it in 100 mL of PBS bu...

Embodiment 5

[0086] Example 5 Animal Anesthesia Experiment

[0087]Only the good water-soluble propofol prodrugs shown by the solubility measurement results are investigated here. Twelve healthy SD rats, weighing 180-200 g, were selected and randomly divided into five groups, with 3 rats in each group, and were raised under normal conditions before the test and during the observation period. Compounds 1f, 2e and 2f with good water solubility were respectively dissolved in physiological saline for injection. The commercially available propofol emulsion was used as a reference substance, and the doses were all measured according to the effective dose of propofol 13 mg / kg (0.073 mmol / kg). Tail vein injection was used to observe the phenomenon of anesthesia in the rats, and the duration of anesthesia was recorded. The experimental results are shown in Table 2.

[0088] Table 2 Anesthesia effect of different compounds on rats

[0089] compound

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Abstract

Belonging to the field of organic chemistry and pharmaceutical chemicals, the invention discloses preparation and application of a monodisperse polyethylene glycol monomethyl ether modified propofol prodrug with a novel structure. Monodisperse polyethylene glycol monomethyl ether and propofol can be connected by an in-vivo degradable chemical bond to prepare a series of carbonic ester type and acetic ester type prodrugs respectively. By adjusting the length of the monodisperse polyethylene glycol monomethyl ether chain, the method can synthesize corresponding water-soluble propofol prodrugs, the longer the monodisperse polyethylene glycol monomethyl ether chain is, the better the water solubility is, along with the improvement of the water solubility, the prodrug can be made into aqueous solution preparations so as to avoid the defects of fat emulsion in propofol fat emulsions. The method provided by the invention has the advantages of simple reaction, mild conditions and low cost, andis convenient for industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis and pharmaceutical chemical industry, in particular to the preparation and application of a propofol prodrug modified with monodisperse polyethylene glycol monomethyl ether with a novel structure. Background technique [0002] Propofol (2,6-diisopropylphenol) is a general anesthetic for intravenous injection of an alkylphenol, which has been widely accepted as a short-acting intravenous anesthetic. Short, the patient has the advantages of no side effects such as coughing and hiccups. In addition to its various advantages as an anesthetic, propofol has a series of other valuable applications. It has also been reported to have antiemetic, anxiolytic, neuroprotective, Itching, analgesia, inhibition of platelet aggregation, inhibition of inducible NO production and other effects, but it has a high degree of fat-soluble, almost insoluble in water, clinically, propofol is prepared into oil-in-w...

Claims

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Application Information

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IPC IPC(8): C07C69/96C07C69/708C07C67/08C07C68/00A61P25/20A61P23/00
CPCC07C69/708C07C69/96
Inventor 江中兴邓涛
Owner WUHAN UNIV
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