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Aminoevodiamine polymer micelle and its preparation method and application

An aminoevodiamine and polymer glue technology, which can be used in drug combination, drug delivery, pharmaceutical formulation and other directions, and can solve problems such as the effect of antitumor activity

Active Publication Date: 2022-08-02
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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  • Aminoevodiamine polymer micelle and its preparation method and application
  • Aminoevodiamine polymer micelle and its preparation method and application
  • Aminoevodiamine polymer micelle and its preparation method and application

Examples

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Synthetic example

[0033] Referring to 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, two compounds with nitro groups, 2-nitroevodiamine (7a) and 10-methoxy-2-nitroevodiamine (7b), were synthesized; then 2-aminoevodiamine (8a) was generated by 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]In a 250mL single-necked flask, add tryptamine (1a) 4g (M=160.22, 24.97mmol), ethyl formate 120mL (both reactant and solvent), clear light yellow liquid, heat to reflux, reflux at 60°C for 18 hours. Rotary steam to obtain oily liquid. Add dichloromethane to the flask to dissolve, and under the condition of 0-5 ℃ ice-salt bath, drop in 10ml POCl with a dropping funnel (after 10 minutes) 3 , the reaction was carried out in ...

Embodiment 1

[0043] Example 1 Synthesis of Aminoevodiamine Polymer Conjugates

[0044] Carboxyl- 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 nitrogen protection, using DMAP as catalyst and EDC as dehydrating agent to generate mPEG-CO-NH-EVO and mPEG-CO-NH-EVO-OCH 3 conjugate. The synthetic route is as follows:

[0045]

[0046] 122.38 mg (0.061 mmol) of mPEG-COOH 2000 In 20 mL dry DCM, 39.73 mg (0.125 mmol) 2-NH 2 - EVO was dissolved in 3 mL of DMF, and then 17 mL of dry DCM was added, and magnetic stirring was uniform. Under nitrogen protection, 10 mL of a DCM solution containing 100 mg (0.522 mmol) of EDC and 8 mg (0.066 mmol) of DMAP was slowly added dropwise with a syringe at 0 °C in an ice bath, and reacted at 0 °C for 2 h, and then at room temperature for 48 h. After the reaction, washed with saturated sodium carbonate solution, washed with dilute hydroch...

Embodiment 2

[0053] Example 2 Preparation of polymer micelles

[0054] The amphiphilic polymer micelles were prepared by the solvent evaporation method. 10 mg of mPEG-CO-NH-EVO conjugate was weighed, dissolved in 1 mL of tetrahydrofuran, dropped into 10 mL of stirred ultrapure water, and stirred for 30 min. Then, it was left standing in a fume hood for 20 hours, and the dissolved tetrahydrofuran was volatilized at room temperature, thereby preparing an amphiphilic polymer micelle mPEG-CO-NH-EVO micelle, which was located in water, and after the water volatilized, a pure gel was obtained bundle.

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

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

[0057]

[0058] Characte...

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Abstract

The invention discloses amino evodiamine polymer micelles and a preparation method and application thereof. A 2-nitroevodiamine derivative is prepared from a carboline compound and N-methyl-7-nitrosatinic anhydride. The aminoevodiamine derivative is reduced to obtain aminoevodiamine derivative, and the polymer is reacted with aminoevodiamine to prepare aminoevodiamine polymer conjugate; then the aminoevodiamine polymer conjugate is self-assembled to obtain aminoevodiamine polymer conjugate To improve the water solubility and bioavailability of drugs, combine drugs with nanotechnology, and develop nano-drug loading systems for drug delivery. Nano-drugs can be passively targeted and enriched in tumor tissues through the EPR effect.

Description

technical field [0001] The invention belongs to a drug-loaded micelle, in particular to an aminoevodiamine polymer micelle and a preparation method and application thereof. Background technique [0002] Polymeric micelles (PMs), as a new type of nanocarriers, have the advantages of simple structure, high drug loading, and easy formation of abundant nanostructures. Polymer micelles linked by pH-sensitive ester bonds, hydrazone bonds, amide bonds, reduction-sensitive disulfide bonds and other stimuli-sensitive covalent bonds bind hydrophobic drugs in polymer carriers to facilitate drug delivery and reduce toxicity. CN103284947A relates to the formulation and preparation method of evodiamine nanoemulsion, and the prepared evodiamine nanoemulsion can improve the solubility of medicine, improve bioavailability and pharmacological activity. CN102727454A provides a new drug for the treatment of hyperuricemia and gout-evodiamine dispersible tablet, which is a preparation prepared ...

Claims

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Application Information

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Patent Type & Authority Patents(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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