Neuraminidase inhibitor prodrug and its composition and use

A composition and drug technology, applied in the field of medicine, can solve problems such as limited application and short half-life

Active Publication Date: 2014-06-11
BEIJING PRELUDE PHARM SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, studies have shown that the in vivo half-life of compound 1 is short, only 2-5 hours (see Li, W. et al., Identification of GS4104as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS4071.Antimicrob Agents Chemother, 1998.42(3 ): p.647-653), limiting its use in the treatment of influenza

Method used

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  • Neuraminidase inhibitor prodrug and its composition and use
  • Neuraminidase inhibitor prodrug and its composition and use
  • Neuraminidase inhibitor prodrug and its composition and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: the preparation of compound 1

[0055] Synthetic scheme

[0056]

[0057] 1. Synthesis of Compound 1-10

[0058]

[0059] To a 250-mL 3-neck round bottom flask was added a solution of thiourea (2 g, 26.27 mmol, 1.00 equiv) in THF (50 mL), then NaHl (60%) was added in several portions with stirring at -10-0 °C ( 2.3g). The resulting solution was stirred at -10-0°C for 1 hour. Thereto was added dropwise a solution of di-tert-butyl dicarbonate (12.6 g, 57.73 mmol, 2.20 equiv) in tetrahydrofuran (50 mL) at 0° C. with stirring. The resulting solution was stirred overnight at room temperature, quenched by the addition of 100 mL of water, then extracted with 2x100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, then concentrated under vacuum. Purification of the residue on a silica gel column eluting with ethyl acetate:petroleum ether (1:5-1:2) afforded 1.5 g (21%) of tert-butyl N-([[(tert-butoxy)carbonyl] ...

Embodiment 2

[0071] Embodiment 2: the preparation of compound I2

[0072] Synthetic scheme

[0073]

[0074] 1. Synthesis of compound I2-10

[0075]

[0076] To oseltamivir (4.1g, 10mmol, 1.0eq) and Et 3To a mixture of N (6.1 g, 60 mmol, 6.0 eq) in EtOH (10 mL) was added BrCN (1.1 g, 10 mmol). The mixture was then stirred overnight at room temperature. TLC and LCMS showed the reaction was complete. To the resulting mixture was added brine (50 mL). The mixture was concentrated under vacuum to remove EtOH, then the residue was extracted with DCM (50 mL x 3). The extract was washed with brine (50 mL), washed with Na 2 Drying over SO4 and concentration gave the crude product (3.9 g) as a yellow oil. The residue was used in the next step without purification.

[0077] 2. Synthesis of compound I2

[0078]

[0079] To a solution of compound I2-10 (9 g) and Et3N (8.1 g, 80.02 mmol, 3.0 eq) in EtOH (300 mL) was added NH2OH.HCl (11 g, 80.02 mmol, 3.0 eq). The mixture was stirred...

Embodiment 3

[0081] Embodiment 3: the preparation of compound I3

[0082] Synthetic scheme

[0083]

[0084] 1. Synthesis of compound I3-10

[0085]

[0086] To a 250-mL round bottom flask was added ethyl (3R,4R,5S)-5-amino-4-acetamido-3-(pent-3-yloxy)cyclohex-1-ene-1-carboxylate ( 5 g, 16.00 mmol, 1.00 equiv), KOCN (4 g), acetic acid (50 mL), and water (50 mL). The resulting solution was stirred overnight at 50 °C, concentrated in vacuo, then washed with 100 ml H 2 O dilution. The solid was collected by filtration to yield 1.7 g (30%) of (3R,4R,5S)-5-(carbamoyl)-4-acetamido-3-(pent-3-yloxy)cyclohex-1-ene -1-Ethyl carboxylate as a white solid.

[0087] 2. Synthesis of compound I3-11

[0088]

[0089] Into a 50-mL round bottom flask was added (3R,4R,5S)-5-(carbamoyl)-4-acetylamino-3-(pent-3-yloxy)cyclohex-1-ene-1- A solution of ethyl formate (500 mg, 1.41 mmol, 1.00 equiv) in pyridine (10 mL) and TsCl (1 g, 5.25 mmol, 3.73 equiv). The resulting solution was stirred overni...

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PUM

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Abstract

The invention provides a compound shown as formula Ia, its pharmaceutically acceptable salts, solvates, polymorphs, enantiomer or racemic mixtures. The compound is used as a neuraminidase inhibitor prodrug, and can improve the half-life in the body of a neuraminidase inhibitor. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound, and use of the pharmaceutical composition and the compound in preparation of neuraminidase inhibitor drugs and treatment of related diseases.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to a compound as a prodrug of a neuraminidase inhibitor, a pharmaceutical composition comprising the compound, and the compound and the pharmaceutical composition are used in the preparation of medicine and treatment-related use in disease. Background technique [0002] Influenza, referred to as influenza, is an acute respiratory infectious disease caused by influenza virus. The disease is highly contagious and widely spread, often endemic. In 2009, there were hundreds of millions of patients infected with influenza virus worldwide, and the death toll was about 13,600. Therefore, influenza is one of the important public health problems expected to be solved at present. [0003] It has been found that the lipid envelope of influenza virus has two important glycoproteins, namely hemagglutinin and neuraminidase. Among them, neuraminidase is a kind of sugar hydrolase, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/16C07C279/24C07C277/08C07C291/02A61K31/196A61K31/215A61K31/27A61P31/12A61P31/16
CPCC07C279/16A61K31/215A61P31/12A61P31/16C07C279/24
Inventor 王志岩
Owner BEIJING PRELUDE PHARM SCI & TECH
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