Gemcitabine chemical transfer prodrug, preparation method and applications thereof

A technology of chemical delivery and gemcitabine, applied in chemical instruments and methods, organic chemistry, pharmaceutical formulations, etc., can solve the problems of limiting drug therapeutic effect, limited ability, and inability to fully meet clinical treatment, and achieve the effect of increasing drug content

Active Publication Date: 2015-10-28
SHANGHAI ZHIMENG BIOLOGICAL PHARMA CO LTD
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Problems solved by technology

[0004] At present, many central nervous system drugs, anti-glioma and other brain tumor drugs have limited ability to penetrate the BBB due to low lipophilicity, and cannot effectively diffuse into the brain tissue to exert their drug effects. Increasing the dosage of the drug will cause the enhancement of the toxic and side effects of peripheral drugs. The above factors have greatly limited the therapeutic effect of these drugs.
[0005] The commonly used 1,4-dihydrotrigonelline CDS is unstable to oxygen in the air and in the solution, and the double bond at the 5 and 6 positions is prone to hydration and oxidation, so the drug CDS prepared by this system Poor stability, unable to effectively deliver drugs into the brain, and cannot fully meet the purpose of clinical treatment

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  • Gemcitabine chemical transfer prodrug, preparation method and applications thereof
  • Gemcitabine chemical transfer prodrug, preparation method and applications thereof
  • Gemcitabine chemical transfer prodrug, preparation method and applications thereof

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Embodiment Construction

[0026] The preferred embodiments of the present invention are given below in conjunction with the accompanying drawings to describe the technical solution of the present invention in detail.

[0027] Mechanism of drug operation of the present invention such as figure 1 As shown, the gemcitabine chemical delivery prodrug is based on the oxidation-reduction reaction of dihydropyridine-pyridinium ions, and the drug gemcitabine is connected with the targeting agent 3-quinolinic acid to form a CDS conjugate (reduced gemcitabine chemical delivery prodrug), the high lipid solubility of the conjugate promotes its diffusion into the brain tissue, where the pyridine moiety in the CDS conjugate is absorbed by the coenzyme system (such as NAD(P)H←→NAD(P) + Coenzyme system) is oxidized to a water-soluble onium salt (oxidized gemcitabine chemical delivery prodrug), so that it cannot pass through the BBB and stay in the central nervous system, and release the drug slowly and continuously th...

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Abstract

The present invention discloses a gemcitabine chemical transfer prodrug, a preparation method and applications thereof, wherein the gemcitabine chemical transfer prodrug mainly comprises gemcitabine and a dihydropyridine chemical delivery system. According to the present invention, based on the dihydropyridine-pyridine ion oxidation-reduction reaction, gemcitabine and a targeting agent 3-quinolinic acid are bonded to prepare the reduced gemcitabine chemical transfer prodrug, the conjugate is promoted to diffuse into the brain tissue through the high lipid solubility, and in the brain, the pyridine part in the dihydropyridine brain-targeting chemical delivery system conjugate is oxidized into the oxidized gemcitabine chemical transfer prodrug by a coenzyme system; and the gemcitabine chemical transfer prodrug has effects of improvement of the amount of the drug entering the brain, enhancement of the drug efficacy, reduction of the drug consumption, and reduction of the drug toxic-side effect.

Description

technical field [0001] The invention relates to a prodrug and its application, in particular to a gemcitabine chemical delivery prodrug and its preparation method and application. Background technique [0002] Brain diseases such as brain tumors, central nervous system infections, chronic pain, epilepsy, neurodegenerative diseases and strokes have a huge impact on human health. The current treatment methods mainly include: systemic administration, intrathecal or intracerebral injection, and brain implantation. The latter two techniques require high requirements, are susceptible to infection, and are invasive to brain tissue, which limits their application. Drugs are widely distributed during systemic administration and can easily cause severe toxicity or adverse reactions. In recent years, the research on brain-targeted drug delivery is becoming the most popular targeted research field besides tumor-targeted therapy. However, the first obstacle encountered in the study of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00A61K31/7068A61K47/48A61P25/00A61P35/00
Inventor 陈键
Owner SHANGHAI ZHIMENG BIOLOGICAL PHARMA CO LTD
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