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Conjugate for preventing cisplatin drug-induced deafness and preparation method and application thereof

A technology of conjugates and drug sources, which is applied in the field of hormone conjugates to prepare drugs for the prevention of cisplatin-induced deafness. good capacitive effect

Active Publication Date: 2020-12-29
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it is water-soluble and easy to administer, it is unstable in vivo (Xu M, Guo H, Han J, et al. Structural characterization of metabolites of salvianolic acid B from Salviamiltiorrhiza in normal and antibiotic-treated rats by liquid chromatography–mass spectrometry[J].Journal of Chromatography B,2007,858(1-2):184-198.), it is easy to cause methylation, furan ring opening and hydrolysis reaction, which limits its further clinical application, therefore, it can be considered Structural modification of salvianolic acid B to obtain a more stable prodrug, or dosage form modification to overcome these shortcomings, so as to further develop into a drug that antagonizes ototoxicity
[0005] Existing research results show that although dexamethasone and salvianolic acid B can prevent drug-induced deafness through different channels, the effect of the two alone or in combination to prevent drug-induced deafness is still unsatisfactory.

Method used

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  • Conjugate for preventing cisplatin drug-induced deafness and preparation method and application thereof
  • Conjugate for preventing cisplatin drug-induced deafness and preparation method and application thereof
  • Conjugate for preventing cisplatin drug-induced deafness and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] R is When, the synthetic method of the conjugate shown in formula (I) comprises the following steps:

[0045] (1) Add 250 mg (2.50 mmol) of reactant succinic anhydride and 330 mg (2.70 mmol) of catalyst 4-dimethylaminopyridine into a 25 mL round bottom flask, and add 6 mL of dichloromethane to dissolve. Then add 549mg (1.40mmol) dexamethasone dissolved in 1mL N,N-dimethylformamide, mix well, and react at room temperature under the protection of argon for 12h; after the reaction, distill the solvent off under reduced pressure, add 300mL ethyl acetate and then washed twice with 10 mL of saturated brine; the collected washings were evaporated and concentrated under reduced pressure, purified by silica gel column chromatography, and the eluent was dichloromethane and methanol with a volume ratio of 10:1, and finally dried in vacuo to obtain white intermediate product A;

[0046] (2) Take 206mg (1.52mmol) of the catalyst 1-hydroxybenzotriazole and 192mg (1.52mmol) of the ...

Embodiment 2

[0060] R is When, the synthetic method of the conjugate shown in formula (I) comprises the following steps:

[0061] (1) 392mg (1.00mmol) dexamethasone was dissolved in 78mL ethanol, 257mg (1.20mmol) of oxidant sodium periodate was dissolved in 31mL of deionized water and 2mL of sulfuric acid solution with a concentration of 2mol / L, and then the two The solution was mixed in a 100mL round bottom flask and stirred at room temperature for 24h. After the reaction, the solvent was distilled off under reduced pressure, and 55 mL of brine was added. Adjust the pH of the solution to 12 by adding 1 mol / L sodium hydroxide aqueous solution, add 100 mL of dichloromethane to wash three times, and then adjust the pH to 3 with 1 mol / L hydrochloric acid solution; finally add dichloromethane with a volume ratio of 1:1 Methane and ethyl acetate mixed solution were extracted, the collected extract was evaporated and concentrated under reduced pressure, and dried in vacuo to obtain a white in...

Embodiment 3

[0073] Embodiment 3: (preparation and characterization of self-assembled nanoparticles)

[0074] (1) Preparation of nanoparticles of conjugate D

[0075] Weigh 100 mg of conjugate D and dissolve it in 10 mL of ethanol, and dissolve it completely by ultrasonication. Slowly add the ethanol solution of the conjugate to 40 mL of water for injection, and stir magnetically for 1.5 h at room temperature. The ethanol in was distilled off under reduced pressure, and the resulting solution was the nanoparticles of conjugate D.

[0076] (2) Preparation of nanoparticles of conjugate H

[0077] The preparation method is the same as (1), stirring magnetically at room temperature for 2 h.

[0078] (3) Particle size and potential analysis of nanoparticles

[0079] The experimental method is as follows: after diluting the conjugate H and conjugate D nanoparticle solutions prepared in (1) and (2) 50 times with deionized water, they were placed in a Malvern Nano S90 particle size analyzer, an...

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Abstract

The present invention relates to a conjugate for preventing cisplatin drug-induced deafness, the chemical structure of the conjugate is shown in formula (I). R in the formula (I) is shown in figure 1or shown in figure 2. The conjugate can be prepared into an injection for preventing cisplatin drug-induced deafness through solubilization, and can also be self-assembled to form nanoparticles so asto be directly prepared into an injection for preventing cisplatin drug-induced deafness. The injection provided by the invention has a remarkable effect of preventing cisplatin drug-induced deafness.

Description

technical field [0001] The present invention relates to an organic conjugate, in particular to a hormone conjugate, and the conjugate is suitable for preparing a drug for preventing cisplatin-induced deafness. Background technique [0002] Cisplatin, a platinum-based cytotoxic agent, is still the mainstream of cancer treatment, but cisplatin can cause severe ototoxicity, mainly including hearing impairment such as deafness and tinnitus, vertigo and vestibular dysfunction. The main reason is that its ototoxicity leads to the apoptosis of hair cells. Once the mammalian cochlear hair cells are damaged, they cannot regenerate, resulting in permanent hearing loss. The main direction of drugs for the prevention and treatment of deafness is to control the cause and relieve symptoms. Although many drugs have entered clinical trials, the U.S. Food and Drug Administration (FDA) has not yet approved a drug for the prevention and treatment of deafness. Therefore, it is urgent to find ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/55A61K47/69A61K31/573A61K31/343C07J41/00A61P27/16
CPCA61K47/55A61K47/6929A61K31/573A61K31/343A61K9/0019C07J41/005A61P27/16A61K2300/00Y02P20/55
Inventor 陈钢温露
Owner GUANGDONG PHARMA UNIV
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