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Voriconazole derivative, synthesis method thereof and voriconazole immunogen, preparation method and application thereof

A technology of voriconazole and voriconazole enzyme, applied in the biological field, can solve the problems of difficulty in parameter matching stability of population dynamics, difficulty in establishing PPK guidance, long population cycle, etc., to achieve clinical promotion and use, reduce detection costs, and easy operation Effect

Inactive Publication Date: 2019-06-25
苏州博源医疗科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the group cycle for establishing this model is long, and there are certain difficulties in matching stability between individual differences and group dynamics parameters, and it is costly and difficult to establish a safe and stable PPK guidance
[0007] At present, the commonly used methods for detecting voriconazole are gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC) and enzyme-linked immunoassay (ELISA), etc., but these methods are complicated to operate and widely used in clinical practice. have certain limitations
At present, there is a lack of voriconazole detection reagents with good stability, high sensitivity and strong specificity in the market, especially high-throughput automated detection reagents with good quality

Method used

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  • Voriconazole derivative, synthesis method thereof and voriconazole immunogen, preparation method and application thereof
  • Voriconazole derivative, synthesis method thereof and voriconazole immunogen, preparation method and application thereof
  • Voriconazole derivative, synthesis method thereof and voriconazole immunogen, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Synthesis and Analysis and Identification of Voriconazole Derivatives

[0062] Voriconazole derivatives were synthesized via the following synthetic route:

[0063]

[0064] Concrete synthetic steps are as follows:

[0065] 1) Synthesis of Compound 2:

[0066]

[0067] Compound 1 (5.0g, 14.3mmol), fuming HNO 3 (3mL) and concentrated H 2 SO 4 (15mL) were mixed and stirred at room temperature for 3h; the reacted material was poured into cold saturated NaHCO 3 solution, add NaHCO 3 Adjust the pH to neutral and extract with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain an off-white solid. The resulting residue was purified by flash chromatography (0-50% ethyl acetate: hexanes) to afford compound 2 as a white solid, 5 g (88%).

[0068] 2) Synthesis of compound 3:

[0069]

[0070] Compound 2 (5.0g, 12.7mmol), SnCl 2 (11.5g, 50.8mmol) and EtOH (50mL) were mixed, stirred at ...

Embodiment 2

[0085] Example 2: Synthesis of voriconazole immunogen

[0086] The structural formula of the voriconazole immunogen is shown in formula II:

[0087]

[0088] The voriconazole immunogen is formed by coupling the carrier and the voriconazole derivative prepared in Example 1; in this example, the carrier is bovine serum albumin (BSA).

[0089] The specific steps of the preparation method of the voriconazole immunogen are as follows:

[0090] a. Weigh 5.0 g of potassium dihydrogen phosphate, 10.0 g of disodium hydrogen phosphate, 7.5 g of sodium chloride, and 1.0 g of magnesium chloride, dissolve them in 800 mL of deionized water, adjust the pH to 8.0, and make buffer solution A;

[0091] b. Weigh 5 mg of carrier protein and dissolve it in 10 mL of the above buffer solution A at 0°C to make a carrier protein solution;

[0092] c. Weigh 5 mg of the voriconazole derivative prepared in Example 1, and dissolve it in 300 μl of the above-mentioned buffer solution A at 0° C. to prep...

Embodiment 3

[0095] Example 3: Preparation of anti-voriconazole specific antibody

[0096] The preparation method of anti-voriconazole specific antibody is as follows:

[0097] 1) Dilute the voriconazole immunogen to 0.8 mg / mL with PBS to obtain an antigen solution, then mix 1.5 mL of the antigen solution with an equal amount of Freund's complete adjuvant, and inject the experimental animal rabbit for the first time; 3 weeks later, use Mix 1.5mL antigen solution with the same amount of Freund's incomplete adjuvant for the second injection; then inject once every 5 weeks with 3.5mL antigen solution mixed with the same amount of Freund's incomplete adjuvant, and inject 5 times in the immunization step;

[0098]2) Blood was collected from the immunized experimental animal rabbit and separated and purified to obtain an anti-voriconazole specific antibody with a titer of 1:50000.

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Abstract

The invention discloses a voriconazole derivative, a synthesis method thereof and a voriconazole immunogen, a preparation method and application thereof. An anti-voriconazole specific antibody prepared from the voriconazole derivative has strong specificity and high titer, also has no cross reaction with 92 common interferents, thus reflecting high accuracy, precision, sensitivity and specificity.The voriconazole immunogen can be applied to preparation of an anti-voriconazole specific antibody and the anti-voriconazole specific antibody can be applied to preparation of a voriconazole detection reagent. The detection reagent can realize high throughput and rapid detection of voriconazole on a fully automatic biochemical analyser.

Description

technical field [0001] The invention relates to a voriconazole derivative, a synthesis method thereof, a voriconazole immunogen, a preparation method and application thereof, and belongs to the field of biotechnology. Background technique [0002] Voriconazole (Voriconazole), its structural formula is as shown in formula IV: [0003] [0004] Voriconazole is a triazole antifungal drug approved by the FDA in 2002. It has good antibacterial activity against Cryptococcus neoformans, Candida, and pathogenic yeasts. It can be used to treat invasive aspergillosis and actinomycetes. Severe infections caused by genus, Fusarium, etc. and non-neutropenic candidemia, and those who are ineffective or intolerable after treatment with other antifungal drugs. [0005] Clinically, the pharmacokinetics of voriconazole presents dose-dependent nonlinear kinetics, resulting in large individual differences. Under the standard dosing regimen, the trough concentration of voriconazole C min A...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07K14/765C07K14/795C07K14/435C07K16/44G01N33/531G01N33/94
Inventor 虞留明张有涛
Owner 苏州博源医疗科技有限公司
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