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Use of neuraminidase inhibitor and neuraminidase inhibitor prodrug

A use and prodrug technology, applied in the preparation of organic compounds, antiviral agents, pharmaceutical formulations, etc., can solve the problems of drug resistance and Tamiflu’s inability to exert antiviral effects

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

For example, mutations (such as R292K, H274Y, etc.) in multiple amino acid residues of the virus NA lead to the resistance of the virus to Tamiflu
[0007] In the N1 subtype of influenza virus NA, it has been confirmed that the H274Y influenza virus strain has shown strong resistance to Tamiflu. The reason is that the mutated H274Y gene can prevent Tamiflu from binding to the virus surface protein, which makes Tamiflu unable to play an antiviral role

Method used

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  • Use of neuraminidase inhibitor and neuraminidase inhibitor prodrug
  • Use of neuraminidase inhibitor and neuraminidase inhibitor prodrug
  • Use of neuraminidase inhibitor and neuraminidase inhibitor prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the preparation of compound 1

[0045] Synthetic scheme

[0046]

[0047] 1. Synthesis of Compound 1-10

[0048]

[0049] 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 NaH (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 h. A solution of di-tert-butyl dicarbonate (12.6 g, 57.73 mmol, 2.20 equiv) in tetrahydrofuran (50 mL) was added dropwise thereto with stirring at 0°C. 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] Amino]...

Embodiment 2

[0063] Embodiment 2: the preparation of compound I2

[0064] Synthetic scheme

[0065]

[0066] 1. Synthesis of compound I2-10

[0067]

[0068] To oseltamivir (4.1g, 10mmol, 1.0eq) and Et 3 To 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.

[0069] 2. Synthesis of compound I2

[0070]

[0071] 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 stirre...

Embodiment 3

[0075] Embodiment 3: the preparation of compound I3

[0076] Synthetic scheme

[0077]

[0078] 1. Synthesis of compound I3-10

[0079]

[0080]To a 250-mL round bottom flask was added ethyl (3R,4R,5S)-5-amino-4-acetylamino-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-acetylamino-3-(pent-3-yloxy)cyclohex-1-ene -1-Ethyl carboxylate as a white solid.

[0081] 2. Synthesis of compound I3-11

[0082]

[0083] 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 ove...

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PUM

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Abstract

The invention provides use of a compound shown as formula Ia or a prodrug thereof in preparation of drugs for the prevention and / or treatment of Tamiflu resistant influenza viruses strain infection, a Tamiflu resistant influenza viruses strain is preferably H1N1 Swine-origin influenza A virus H274Y. The invention also provides a method for the treatment, prevention or delay of virus infection caused by the Tamiflu resistant influenza viruses strain, and the method comprises administering of a therapeutically effective amount of the compound or the prodrug thereof to patients needing the treatment.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to the use of a compound as a neuraminidase inhibitor and a prodrug thereof in preparing medicine and treating related diseases. 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 glycohydrolase. By splitting sialic acid residues, the virus cannot be self-aggregated after being released from the host cell, th...

Claims

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Application Information

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IPC IPC(8): A61K31/196A61K31/215A61K31/27A61P31/12A61P31/16C07C279/16C07C279/24C07C277/08C07C291/02
CPCA61K31/16C07C279/16C07C277/08A61K31/196A61K31/215A61P31/12A61P31/16C07C279/26
Inventor 王志岩
Owner BEIJING PRELUDE PHARM SCI & TECH
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