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Amino evodiamine polymer micelle as well as preparation method and application thereof

A technology of aminoevodiamine and polymer glue, which can be applied in the direction of drug combination, drug delivery, and pharmaceutical formulation, and can solve the problems of anti-tumor activity and other issues

Active Publication Date: 2020-09-22
SHAANXI UNIV OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the nanomicelles disclosed in the prior art are all aimed at evodiamine (EVO), and the structure of EVO is modified to obtain derivatives with different positions and different substituents, which have a significant impact on antitumor activity. Modifications mostly focus on the 10th position of the A ring, the 13th position of the B ring, the 14th position of the D ring, the 3rd position of the E ring and the modification of the E ring skeleton

Method used

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  • Amino evodiamine polymer micelle as well as preparation method and application thereof
  • Amino evodiamine polymer micelle as well as preparation method and application thereof
  • Amino evodiamine polymer micelle as well as preparation method and application thereof

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Synthetic example

[0033] See another application submitted by the applicant on the same day, the invention title is aminoevodiamine derivatives and their preparation method and application, which discloses aminoevodiamine.

[0034] First synthesize 2 compounds with nitro groups, 2-nitroevodiamine (7a) and 10-methoxy-2-nitroevodiamine (7b); then generate 2-aminoevodiamine (8a) through reduction reaction and 10-methoxy-2-aminoevodiamine (8b). The synthetic route is as follows:

[0035]

[0036] Synthesis of Compound 3,4-Dihydro-β-carboline (3a)

[0037]Add 4g of tryptamine (1a) (M=160.22, 24.97mmol) and 120mL of ethyl formate (both reactant and solvent) into a 250mL one-necked flask to obtain a clear light yellow liquid, heat to reflux at 60°C for 18 hours. Rotary steaming, an oily liquid was obtained. Add dichloromethane to the flask until it dissolves. Under the condition of 0-5°C ice-salt bath, use the dropping funnel to drop (10 minutes to finish) 10ml POCl 3 , reacted for 2h under ice...

Embodiment 1

[0043] Example 1 Synthesis of aminoevodiamine polymer conjugates

[0044] Carboxy- and methoxy-terminated polyethylene glycol (mPEG-COOH 2000 ) respectively with the aminoevodiamine derivative 2-NH 2 -EVO, 10-OCH 3 -2-NH 2 -EVO reaction, under the protection of nitrogen, use DMAP as catalyst and EDC as dehydrating agent to generate mPEG-CO-NH-EVO and mPEG-CO-NH-EVO-OCH 3 Conjugates. The synthetic route is as follows:

[0045]

[0046] 122.38 mg (0.061 mmol) mPEG-COOH 2000 Dissolved in 20 mL of dry DCM, 39.73 mg (0.125 mmol) of 2-NH 2 - Dissolve EVO in 3mL DMF, add 17mL dry DCM, and stir evenly with magnetic force. Under nitrogen protection, 10 mL of DCM solution containing 100 mg (0.522 mmol) of EDC and 8 mg (0.066 mmol) of DMAP was slowly dripped with a syringe under the condition of 0 °C ice bath, reacted at 0 °C for 2 h, and then reacted at room temperature for 48 h. After the reaction was complete, wash with saturated sodium carbonate solution, then dilute hydro...

Embodiment 2

[0053] The preparation of embodiment two polymer micelles

[0054] Prepare amphiphilic polymer micelles by solvent evaporation method, weigh 10 mg of mPEG-CO-NH-EVO conjugate, dissolve in 1 mL of tetrahydrofuran, drop into stirred 10 mL of ultrapure water, and continue stirring for 30 min. Then let it stand in a fume hood for 20 hours, and volatilize the dissolved tetrahydrofuran at room temperature, thereby preparing the amphiphilic polymer micelles mPEG-CO-NH-EVO micelles, which are located in water, and after the water volatilizes, a pure gum is obtained. bundle.

[0055] mPEG-CO-NH-EVO-OCH 3 The preparation of micelles was the same as above.

[0056] As a contrast, replace the 2-NH of the present invention with existing aminoevodiamine derivatives 2 -EVO, through the same method, mPEG-CO-NH-ENH micelles are obtained; the chemical structural formula of the existing aminoevodiamine derivatives is as follows:

[0057]

[0058] Characterization of polymer micelles

[...

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Abstract

The invention discloses an amino evodiamine polymer micelle as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing a 2-nitro evodiamine derivative from a carboline compound and N-methyl-7-nitro isatoic anhydride, reducing the 2-nitro evodiamine derivative to obtain an amino evodiamine derivative, and reacting a polymer with amino evodiamine to prepare an amino evodiamine polymer conjugate; and then carrying out self-assembly on the amino evodiamine polymer conjugate to obtain the amino evodiamine polymer micelle. The water solubility and bioavailability of a drug are improved, the drug is combined with a nanotechnology, a nano drug loading system is developed for drug delivery, and the nano drug can be passively enriched intumor tissues in a targeting manner through an EPR effect.

Description

technical field [0001] The invention belongs to drug-loaded micelles, in particular to aminoevodiamine polymer micelles, a preparation method and application thereof. Background technique [0002] As a new type of nanocarrier, polymeric micelles (PMs) have the advantages of simple structure, high drug loading capacity, and easy formation of rich nanostructures; according to the hypoxic and slightly acidic environment in tumor tissue, the following pH-sensitive ester bonds, hydrazone bonds, amide bonds, reduction-sensitive disulfide bonds and other stimuli-sensitive covalently bonded polymer micelles bond hydrophobic drugs in polymer carriers to facilitate drug delivery and reduce toxicity. CN103284947A relates to a formula and a preparation method of evodiamine nanoemulsion, and the prepared evodiamine nanoemulsion can improve the solubility of medicines, bioavailability and pharmacological activity. CN102727454A provides a new drug for treating hyperuricemia and gout-evod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K31/519A61K47/60A61K47/69A61P35/00C08G65/333
CPCA61K9/1075A61K47/6907A61K31/519A61K47/60A61P35/00C08G65/33327
Inventor 郭惠杨若澜马晶晶
Owner SHAANXI UNIV OF CHINESE MEDICINE
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