Cabazitaxel-fatty acid conjugate and nano preparation thereof

A technology of cabazitaxel and fatty acids, which is applied in the field of medicine, can solve the problems of strong toxic and side effects, poor targeting, and poor stability, and achieve the effect of improving curative effect, optimal effect, and small particle size

Pending Publication Date: 2022-03-04
スゾウユタイファーマシューティカルテクノロジーカンパニーリミテッド
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Based on the above background technology, for existing cabazitaxel preparations Due to the shortcomings of strong toxic and side effects, poor stability, and poor targeting, the present invention connects cabazitaxel to linoleic acid through a disulfide bond to prepare a new cabazitaxel-fatty acid conjugate

Method used

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  • Cabazitaxel-fatty acid conjugate and nano preparation thereof
  • Cabazitaxel-fatty acid conjugate and nano preparation thereof
  • Cabazitaxel-fatty acid conjugate and nano preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Synthesis of Cabazitaxel-Oleic Acid Conjugate (CTX-OA) Directly Connected by Ester Bonds

[0039] Accurately weigh OA (118.6 mg, 0.42 mmol), place DCC and DMAP in a 50 mL eggplant-shaped flask, add 10 mL of anhydrous CH 2 Cl 2 , in N 2Treated in an ice-water bath for 1 h under the protection of Subsequently, CTX (350 mg, 0.42 mmol) was accurately weighed and added to the above reaction solution, under N 2 Under the protection, the reaction was carried out at 25 °C for 48 h, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, washed with saturated NaCl water for 3 times, and then washed with anhydrous Na 2 SO 4 Dry, filter to remove insolubles, and spin dry the filtrate to obtain a crude product. The crude product was purified with the preparation solution to obtain the final product, cabazitaxel oleate (CTX-OA), with a yield of 45.4% and a purity of 99.42%. The structure is shown in the figure. The high-resol...

Embodiment 2

[0041] Example 2: Synthesis of cabazitaxel-oleic acid conjugate (CTX-SS-OA) linked by disulfide bonds

[0042] Precisely measure ethylene glycol (90 mL, 1.61 mol) and place it in a 250 mL three-neck flask, weigh p-toluenesulfonic acid and place it in the three-neck flask, and raise the temperature of ethylene glycol to 110°C. OA (5000 mg, 17.7 mmol) was precisely weighed, dissolved in toluene, and the OA dissolved in toluene was added dropwise to a three-necked flask. After the reaction is complete, the crude product is purified by silica gel column chromatography, and the target product (Z)-oleic acid-2-hydroxyethyl ester is collected. Weigh EDCI, HOBt, DMAP and (Z)-oleic acid-2-hydroxyethyl ester into an eggplant-shaped bottle of dithioglycolic anhydride to obtain a crude product. The target product (2-oxo-2-(2-((Z)-oleoyloxy)ethoxy)ethanedithio)acetic acid was collected by purification. The reaction product (2-oxo-2-(2-((Z)-oleoyloxy)ethoxy)ethanedithio)acetic acid was pl...

Embodiment 3

[0044] Example 3: Synthesis of cabazitaxel-linoleic acid conjugate (CTX-SS-LA) linked by disulfide bonds

[0045] Precisely measure ethylene glycol (90 mL, 1.61 mol) and place it in a 250 mL three-neck flask, weigh p-toluenesulfonic acid and place it in the three-neck flask, and raise the temperature of ethylene glycol to 110°C. LA (5000 mg, 17.7 mmol) was accurately weighed, dissolved in toluene, and the LA dissolved in toluene was added dropwise to a three-necked flask. After the completion of the reaction, the crude product was purified by silica gel column chromatography, and the target product (9Z, 12Z)-linoleic acid-2-hydroxyethyl ester was collected. Weigh EDCI, HOBt, DMAP and (9Z, 12Z)-linoleic acid-2-hydroxyethyl ester in an eggplant-shaped bottle of dithioglycolic anhydride to obtain a crude product. The target product (2-oxo-2-(2-((9Z,12Z)-linoleoyloxy)ethoxy)ethanedithio)acetic acid was collected by purification. The reaction product (2-oxo-2-(2-((9Z,12Z)-linoleo...

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Abstract

The invention belongs to the technical field of medicines, relates to an antitumor drug cabazitaxel-fatty acid conjugate as well as a preparation method and application thereof, and further relates to a nano preparation of the cabazitaxel-fatty acid conjugate and application thereof. The fatty acid is oleic acid or linoleic acid. In the cabazitaxel-fatty acid conjugate disclosed by the invention, hydroxyl of cabazitaxel is connected with carboxyl of oleic acid or linoleic acid through a disulfide bond. The cabazitaxel-linoleic acid conjugate or the cabazitaxel-linoleic acid conjugate can be self-assembled into nanoparticles, and the preparation is simple in preparation process and easy to industrialize; the sensitive drug release of the intracellular environment of a tumor part can be realized, the anti-tumor cell activity is higher, and the in-vivo pharmacokinetic property is better; most importantly, the nano preparation shows higher in-vivo tumor inhibition activity, and shows a more excellent in-vivo safety effect of the preparation at the same time.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an antitumor drug cabazitaxel-fatty acid conjugate, a preparation method and application thereof, and a nano-formulation of the cabazitaxel-fatty acid conjugate and application thereof. Background technique [0002] In June 2010, the U.S. Food and Drug Administration (FDA) approved the cabazitaxel injection (trade name) produced by French Sanofi-Vanante. ) in combination with prednisone for the treatment of hormone-resistant prostate cancer. Due to the poor water solubility of cabazitaxel (CTX), it is necessary to dissolve cabazitaxel in Tween 80 first, dilute with 13% ethanol solution, and then perform secondary dilution with normal saline or 5% aqueous glucose solution. There are many defects in this preparation: ① Tween 80 in the preparation can easily cause allergic reactions, and patients need to take anti-allergic treatment before administration, and the preparation can al...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/24A61K31/337A61K9/51A61P35/00B82Y5/00
CPCA61K47/542A61K47/24A61K31/337A61K9/5123A61K9/5146A61P35/00B82Y5/00
Inventor 邱诗王永军何仲贵孙进杨金诚
Owner スゾウユタイファーマシューティカルテクノロジーカンパニーリミテッド
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