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Phosphoramido pyridine derivative, and preparation method, medical composition and application thereof in antifungal agent

A technology of phosphonamidopyridine and derivatives, applied to phosphonamidopyridine derivatives, its preparation and pharmaceutical composition and application in antifungal agents, can solve the toxic and side effects of amphotericin B, limited application, resistance to Low drug rate and other problems, to achieve excellent physical and chemical properties and in vivo antifungal activity, strong inhibitory activity, and broad antifungal spectrum effects

Inactive Publication Date: 2012-11-28
姜远英
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although amphotericin B and its liposome have a wide antibacterial spectrum and the lowest drug resistance rate, they are known as the "gold standard" for the treatment of deep fungal infections, but severe side effects, especially irreversible nephrotoxicity, greatly limit the use of amphotericin B in clinical application
Echinocandin antifungal drugs are new antifungal drugs developed in recent years. They have the characteristics of high efficiency and low toxicity, but they are expensive, which limits their clinical application. medication

Method used

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  • Phosphoramido pyridine derivative, and preparation method, medical composition and application thereof in antifungal agent
  • Phosphoramido pyridine derivative, and preparation method, medical composition and application thereof in antifungal agent
  • Phosphoramido pyridine derivative, and preparation method, medical composition and application thereof in antifungal agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Phosphonamidopyridine Derivatives 8 and its salt Synthesis

[0059] Step 1: Compound Synthesis

[0060] Add 2-(3-(6-chloropyridine)) acetate (1.8g, 10mmol), 3,5-difluorobenzyl zinc bromide (22mL 0.5M THF solution, 11 mmol) and Pd(PPh3)4 (600 mg, 0.5 mmol) were stirred at reflux overnight. After cooling, the mixture was washed successively with water, saturated aqueous sodium bicarbonate solution and brine, concentrated to dryness, applied to ISCO combiflash and eluted with 0-20% ethyl acetate petroleum ether eluent to obtain 1.8 g of the product. MS [M+H] 278.

[0061] Step 2: Compound Synthesis

[0062] The ester (1.4g, 5mmol) obtained by the above method was dissolved in 10mL of DMF, potassium carbonate (0.7g, 5mmol) was added, methyl iodide (0.7g, 5mmol) was added dropwise, stirred at room temperature overnight, poured into 20mL of ice water, ethyl acetate Extract the ester, wash the organic phase with saturated brine, concentrate to dryness, add 10 mL of...

Embodiment 2

[0079] Phosphonamidopyridine Derivatives 11 and its magnesium salt Synthesis

[0080] Step 1: Compound Synthesis

[0081] 2-(3-(6-Chloropyridine)) acetate (18.5 g, 100 mmol) was added to 3,5-difluorophenol (14.3 g, 110 mmol) and potassium tert-butoxide (12.5 g, 110 mmol) in DMF (200mL) solution, heated and stirred at 70°C for 6 hours, cooled and poured into 500mL of ice water, filtered, the solid was washed with saturated ice-sodium carbonate aqueous solution, the solid was recrystallized with ethyl acetate, and dried to obtain 22g. MS [M+H] 280.

[0082] Step 2: Compound Synthesis

[0083] The 2-(6-(3,5-difluorophenoxy)pyridyl)methyl acetate (2.8g, 10mmol) obtained above was dissolved in 50mL of acetonitrile, 1.4g of potassium carbonate (2.8g, 20mmol) was added, and stirred for 15 Minutes later, 1,2-dibromoethane (1.9 g, 10 mmol) was added, stirred and refluxed for 3 hours, cooled and filtered, and the filtrate was concentrated to dryness. 1.5 g of the residue was ...

Embodiment 3

[0091] Preparations for Injection

[0092] components

weight

active ingredient

10mg

Sodium chloride

50mg

Water for Injection

q.s

[0093] Preparation method: Dissolve the active ingredient and sodium chloride in an appropriate amount of water for injection, filter the resulting solution, and fill it into containers (ampoules, infusion containers, etc.) under aseptic conditions.

[0094] The active ingredients specifically refer to phosphonamidopyridine derivatives 1-12 and salts thereof.

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Abstract

The invention provides a phosphoramido pyridine derivative represented by a structural formula (I) and salt thereof. In the formula, R1 represents a hydrogen atom, a halogen atom, cyano, amino, R4-NH-, R5-O-, C1-6 alkyl, hydroxyl C1-6 alkyl, C1-6 alkoxy or C1-6 alkoxy C1-6 alkyl; R4 represents C1-6 alkyl, hydroxyl C1-6 alkyl or C1-6 alkoxy C1-6 alkyl; R5 represents C1-6 alkyl or C1-6 alkoxy C1-6 alkyl; R2 and R3 are selected from a hydrogen atom, C1-6 alkyl or C1-6 alkoxy, or R2 and R3 form a C3-8 ring; and X represents a single bond, methylene, an oxygen atom, a sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-. The invention also provides a preparation method of the phosphoramido pyridine derivative and the salt thereof, a medical composition using the phosphoramido pyridine derivative and the salt thereof as the active ingredient, and application thereof in the preparation of antifungal medicaments. Compared with the conventional clinically applied antifungal medicaments, the compound has the advantages of high efficiency, low toxicity, wide antifungal spectrum, high physical and chemical property, fine in-vivo antifungal activity and the like.

Description

technical field [0001] The invention relates to a phosphonamidopyridine derivative and its salt, a preparation method thereof, a pharmaceutical composition containing the compound as an active ingredient, and their application in the preparation of antifungal drugs. Background technique [0002] In recent years, the widespread clinical application of broad-spectrum antibiotics, hormonal drugs, immunosuppressants and tumor chemotherapy drugs has led to an increase in the number of immunocompromised patients year by year. In addition, more and more biological materials such as catheters are used in the human body, making deep The incidence of fungal infection has increased substantially and has become one of the leading causes of death in immunocompromised patients as described above. At present, there are few drugs available for clinical treatment of deep fungal infections, and the side effects are large. Coupled with the increasingly serious phenomenon of fungal drug resista...

Claims

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Application Information

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IPC IPC(8): C07F9/6558C07D213/75A61K31/675A61P31/10
Inventor 姜远英张锐豪常英陆峰安毛毛
Owner 姜远英
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