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Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof

A technology of compounds and compositions, applied in antifungal agents, organic chemistry, pharmaceutical formulations, etc., can solve problems such as unclear mechanism of action, achieve strong antifungal activity, good safety, good pharmacokinetic properties and safety Effect

Active Publication Date: 2012-10-31
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Although the site of action of voriconazole appears to be primarily restricted to the retina, its mechanism of action remains unclear

Method used

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  • Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof
  • Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof
  • Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation and identification test of embodiment 1, formula 1 compound

[0054] Step 1, add 2-chloro-2,4-difluoroacetophenone (27.3g, 0.14mol), 3,5 dibromo-1H-[1,2,4]triazole ( 34g, 0.15mol), potassium carbonate (27.6g, 0.2mol), tetrabutylammonium bromide (2.0g) and 300ml of dichloromethane, and stirred at reflux for 8 hours. Cool, filter, filter residue with CH 2 Cl 2 Wash, combine the organic layers, wash with water, dry, concentrate to dryness, and recrystallize with petroleum ether / ethyl acetate (1 / 1, 200ml) to obtain 35.0 g of a light yellow solid, which is directly used in the next step without purification .

[0055] Step 2, (2R,3S / 2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(3,5- Synthesis of Dibromo-1H-[1,2,4]-triazol-1-yl)butan-2-ol

[0056] Under nitrogen, the ethane solution (80ml, 0.2mol) of 2.5M n-butyllithium was added in the three-necked flask, and the tetrahydrofuran 100ml solution of diisopropylamine (20g, 0.2mol) was add...

Embodiment 2

[0061] Embodiment 2, preparation of the injection comprising the compound of formula 1

[0062] With the compound of formula 1 as the active ingredient, the injection is prepared according to the following formula and preparation process:

[0063] 2.1 Specifications: Each bottle contains 0.1g of new voriconazole.

[0064] 2.2 Composition and formula of injection:

[0065] Neovoriconazole (compound of formula 1) 100g

[0066] Ethanol 4L

[0067] Water for injection 20L

[0068] Made 1000 pieces

[0069] 2.3 Preparation process of injection:

[0070] In the aseptic operation room, weigh 100 g of the new voriconazole raw material (compound of formula 1), add 4 L of ethanol, stir to dissolve, add 30 g of activated carbon, stir for 30 minutes, filter and decarbonize, pass the filtrate through a 0.22 μm sterile membrane, Enter the 100-level clean tank; slowly add 20L of water for injection (refrigerated in the refrigerator) to the above solution, stir while adding, continue ...

Embodiment 3

[0071] Embodiment 3, comparative test of the adverse reaction rate of the compound of formula 1 and the original voriconazole compound

[0072] Under two different modes of administration (A oral administration / B intravenous infusion), 391 patients with acute invasive aspergillosis were given the new voriconazole compound (200 examples) shown in formula 1 of the present invention and the original voriconazole compound respectively. Product (original voriconazole compound, 191 cases) treatment, followed by other approved antifungal drug treatment, and evaluated the adverse reactions of formula 1 compound (180 cases) and original voriconazole (196 cases) in the treatment of esophageal candidiasis . The laboratory treatment effects of the compound of formula 1 and the original voriconazole compound are basically close, but the adverse reactions are greatly different. The specific comparison experiment results are shown in the following table:

[0073] Table 3. Comparative tes...

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Abstract

The invention relates to a novel broad-spectrum antifungal medicine compound, a broad-spectrum antifungal medicine composition, an application of the compound or the composition in the preparation of a broad-spectrum antifungal medicine, and an application of the compound or the composition in the preparation of a medicine used for treating severe invasive infection (comprising Candida krusei) caused by invasive aspergillosis and / or Fluconazole-resistant Monilia and / or severe infection caused by Scedosporium and fusarium. The novel broad-spectrum antifungal medicine compound and the broad-spectrum antifungal medicine composition have extensive and strong antifungal activity and better dynamic property and safety. For deep mycotic infection, the novel broad-spectrum antifungal medicine compound and the broad-spectrum antifungal medicine composition are better than the original voriconazole in the aspects of the antibiotic activity and the medicine resistance and is better than amphotericin B in the aspects of safety and effectiveness; and compared with the formerly applied voriconazole, Fluconazole, itraconazole and amphotericin B, the novel broad-spectrum antifungal medicine compound and the broad-spectrum antifungal medicine composition have reinforced medicine effect, less adverse reaction and good safety.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically, the present invention relates to a new broad-spectrum antifungal drug compound, a broad-spectrum antifungal drug composition, the application of the compound or composition in the preparation of a broad-spectrum antifungal drug, and the compound or composition In the preparation for the treatment of invasive aspergillosis and / or serious invasive infections caused by fluconazole-resistant Candida species (including Candida krusei) and / or severe infections caused by Actinomycetes and Fusarium species application in medicines. Background technique [0002] In view of the current global incidence of severe fungal infections continues to rise, especially the high mortality of fungal infections in immunocompromised populations (such as cancer patients, AIDS patients, organ transplant patients, etc.), the epidemiology of global pathogens has undergone significant changes: Cand...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14A61K31/506A61P31/10
Inventor 陆文歧黄慧敏
Owner LIVZON PHARM GRP INC
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