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Water-soluble target-activated paclitaxel derivatives and their preparation and use

A paclitaxel derivative and water-soluble technology, applied in the field of anti-tumor drugs and drugs, can solve the problems of neutropenia, allergic reactions, toxic and side effects, etc., and achieve the effects of reduced toxicity, weakened toxicity, blood stability and low toxicity

Active Publication Date: 2017-06-16
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 this class of drugs has serious side effects and sensitization reactions, for example: paclitaxel has bone marrow toxicity, causes neutropenia, has neurotoxicity and cardiovascular toxicity, and can cause allergic reactions, spilling out of blood vessels can cause local Inflammation, hair loss, fatigue and liver toxicity

Method used

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  • Water-soluble target-activated paclitaxel derivatives and their preparation and use
  • Water-soluble target-activated paclitaxel derivatives and their preparation and use
  • Water-soluble target-activated paclitaxel derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Synthesis of water-soluble targeted-activated paclitaxel

[0028] 1) Synthesis of two (2-methoxyethoxyacetyl)-L-lysine ethyl ester (I)

[0029] Dissolve 2-(2-methoxyethoxy)acetic acid (161mg, 1.2mmol) in N,N-dimethylformamide (10mL), and after cooling in an ice bath, add 2-(7- Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (462mg, 1.2mmol), N,N-diisopropylethylamine (313mg, 2.4mmol) and L-lysine ethyl ester dihydrochloride (100mg, 0.4mmol), after addition, stirred at room temperature overnight, evaporated the solvent under reduced pressure, and purified the crude product by a reverse-phase preparative column to obtain I (128mg, yield: 77.8%) .

[0030] 2) Synthesis of two (2-methoxyethoxyacetyl)-L-lysine (II)

[0031] Dissolve bis(2-methoxyethoxyacetyl)-L-lysine (122mg, 0.3mmol) in tetrahydrofuran (15mL), cool to 0°C and add dropwise lithium hydroxide (39mg, 0.9mmol) Aqueous solution (5 mL), stirred at room temperature for 2 hours. ...

Embodiment 2

[0047] Example 2 Comparison of the performance of the water-soluble target-activated paclitaxel derivatives prepared in the examples of the present invention and the reference compound

[0048] (1) Sample processing

[0049] The water-soluble target-activated paclitaxel derivatives prepared in the examples of the present invention, compounds S1, S2, S3 and S4 (prepared in Examples 10-11) and the above-mentioned reference compounds C1, C2, C3, C4, C5, 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 schemes: solvent 1 (water for injection) or solvent 2 (45% alcohol, 55% water for injection). 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 injection to the required concentration, while the comparison compounds (C1, C2, C3, C4, ...

Embodiment 3

[0058] Example 3 S1, S2, S3 and S4 (prepared in Examples 10-11) content determination method and content range.

[0059] S1, S2, S3 and S4 use analytical HPLC (Agilent 1220 (Agilent 1220series), 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

The invention discloses water soluble targeting-activated taxol derivatives as well as a preparation method and use thereof. The water soluble targeting-activated taxol derivatives have a following structural formula as shown in the specification, wherein the formula of taxol is also described in the specification, R1 is Ala, Thr, Val or Ile; R2 is Ala, Thr, Val or Asn; and n is equal to 1-150. Compared with taxol, the water soluble targeting-activated taxol derivatives provided by the invention become water soluble type anti-tumor targeting drugs, have specific activation characteristic and immunological enhancement characteristic, and good clinical application prospect, and is greatly improved in the drug action of inhibiting the tumor growth and metastasis, and greatly lowered in toxicity.

Description

technical field [0001] The present invention relates to medicines, in particular to an antitumor medicine, in particular to a water-soluble target-activated paclitaxel derivative, a preparation method thereof, and an application in the preparation of antitumor medicines. Background technique [0002] Paclitaxel is an effective antineoplastic drug widely used at present. It is mainly used in the treatment of various solid tumors such as ovarian cancer and breast cancer. All have certain curative effect. However, because this class of drugs has serious side effects and sensitization reactions, for example: paclitaxel has bone marrow toxicity, causes neutropenia, has neurotoxicity and cardiovascular toxicity, and can cause allergic reactions, spilling out of blood vessels can cause local Inflammation, hair loss, fatigue and liver toxicity. Therefore, its dosage must be limited in clinical application. Therefore, it is necessary to provide a paclitaxel drug that can reduce th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/11A61K31/337A61K47/64A61P35/00
Inventor 刘辰刘源
Owner 上海亲合力生物医药科技股份有限公司