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Paclitaxel derivatives activated by tumor microenvironment targeting and their preparation and use

A paclitaxel derivative and tumor microenvironment technology, applied in the field of medicinal chemistry and paclitaxel anti-tumor drugs, can solve problems such as toxic and side effects, and achieve the effect of reducing toxicity

Active Publication Date: 2017-05-03
上海亲合力生物医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because paclitaxel drugs have serious side effects and adverse reactions, such as neutropenia caused by bone marrow toxicity, neurotoxicity, cardiovascular toxicity, and allergic reactions, local inflammation, hair loss, fatigue and liver toxicity, etc., it is limited clinical use of the drug

Method used

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  • Paclitaxel derivatives activated by tumor microenvironment targeting and their preparation and use
  • Paclitaxel derivatives activated by tumor microenvironment targeting and their preparation and use
  • Paclitaxel derivatives activated by tumor microenvironment targeting and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Synthesis of paclitaxel activated by tumor microenvironment targeting

[0031] 1) Synthesis of (R)-2-(2-(R)-(benzyloxycarbonyl) amino) propionylamino) propionic acid methyl ester (I)

[0032]Dissolve N-benzyloxycarbonyl-L-alanine (100g, 0.45mol) in N,N-dimethylformamide (3L), and add 1-hydroxybenzotriazole (72.6g, 0.54 mol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (103.3g, 0.54mol), stirred and reacted at 0-5°C for 1 hour, then added dropwise L - Alanine methyl ester (46.2g, 0.45mol) and N,N-diisopropylethylamine (173.8g, 1.34mol) in N,N-dimethylformamide (1L) solution, dropwise complete After stirring at room temperature (25°C) for 10 h, the solvent was evaporated under reduced pressure, and the crude product was dissolved in dichloromethane (2 L), washed successively with saturated ammonium chloride solution, water and saturated sodium chloride solution, and the organic phase was washed with anhydrous After drying over sodium sulfate...

Embodiment 2

[0057] Example 2 Comparison of the performance of paclitaxel derivatives with tumor microenvironment targeting activation prepared in the examples of the present invention and control compounds

[0058] (1) Sample processing

[0059] The tumor microenvironment-targeted paclitaxel derivatives prepared in the examples of the present invention, compounds S1, S2, S3 and S4 (prepared in Examples 10-11) and the control compounds C1, C2, C3, C4, and C5 prepared above , C6. After freeze-drying (-70°C), subpackage in a sterile room. Before animal experiments, S1, S2, S3 and S4 can be reconstituted in the sterile room according to the following two solvent solutions: solvent 1 (50% water for injection, 42% to 49% alcohol, 1% to 8% Tween 80 ) or solvent 2 (50% water for injection, 42%-49% propylene glycol, 1%-8% Tween 80). S1, S2, S3 and S4 can be completely dissolved in solvent 1 and solvent 2, and the reconstitution concentration can reach 10 mg / ml, and then diluted with water for in...

Embodiment 3

[0066] Example 3 S1, S2, S3 and S4 (prepared in Examples 10-11) content determination method and content range.

[0067] S1, S2, S3 and S4 use analytical HPLC (Agilent 1220 (Agilent1220series), C8 column 5μm, 4.6mm ID x250mm, mobile phase is 0-95% acetonitrile (ACN) with a purity of 95%-99%).

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Abstract

Tumor microenvironment targeted activation docetaxel derivatives, a preparing method thereof and uses of the derivatives are disclosed. The general formula of the docetaxel derivatives is shown in the specification, wherein a formula shown in the specification is docetaxel, R1 is Ala, Thr, Val or Ile; R2 is Ala, Thr, Val or Asn; and n is 1-300. Compared with the docetaxel, the docetaxel derivatives have characteristics of an anti-tumor targeting property, a specific activation property and immunological enhancement, efficacy of the docetaxel derivatives for inhibiting tumor growth and metastasis is largely improved, and toxicity of the docetaxel derivatives is largely reduced. The docetaxel derivatives have a good application prospect.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to paclitaxel anti-tumor drugs, in particular to paclitaxel derivatives activated by tumor microenvironment targeting and their preparation and application Background technique [0002] Paclitaxel is an effective antineoplastic drug widely used at present. It is mainly used for various solid tumors such as ovarian cancer and breast cancer, and also for lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma, and brain tumors. Certain curative effect. However, because paclitaxel has serious side effects and adverse reactions, such as neutropenia caused by bone marrow toxicity, neurotoxicity, cardiovascular toxicity, and allergic reactions, local inflammation, alopecia, fatigue and liver toxicity, etc., it is limited clinical use of such drugs. Therefore, in order to make better use of paclitaxel, it is necessary to study targeted activating drugs that can reduce the t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/083A61K31/337A61K47/64A61P35/00
Inventor 刘辰刘源
Owner 上海亲合力生物医药科技股份有限公司