Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application

A compound, cyclohexene carboxylic acid technology, applied in the field of new cyclohexene compounds, can solve problems such as no cyclohexene compounds

Inactive Publication Date: 2013-03-13
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, in the published reports, there is no synthesis of cyclohexene compounds containing alkyl and amido substitutions at the C-4' position, and no research on the inhibitory activity of these new compounds on influenza virus neuraminidase

Method used

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  • Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application
  • Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application
  • Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0088] Another specific embodiment provides an intermediate compound with general formula 5 for preparing the compound of general formula I:

[0089]

[0090] Formula 5

[0091] or pharmaceutically acceptable salts thereof, and resolved enantiomers and purified diastereomers, wherein:

[0092] R 1 Can be H or C 1-12 Alkyl;

[0093] Boc may be t-butoxycarbonyl; and

[0094] R 4 Can be -(CH 2 ) n CO 2 H, -(CH 2 ) n P(O)(OH) 2 ,-(CH 2 ) n CO 2 R 1a , or -(CH 2 ) n P(O)(OR 1a ) 2 , where R 1a Can be H or C 1-6 Alkyl, n is an integer from 0 to 4, or a salt of the above groups. Another specific embodiment of the present invention provides intermediate compounds with general formula 6 for the preparation of compounds of general formula I:

[0095]

[0096] Formula 6

[0097] or pharmaceutically acceptable salts, and resolved enantiomers and purified diastereomers, wherein

[0098] R 1 Can be H or C 1-12 Alkyl;

[0099] R 2 Can be H, -C(O)R 1a , -C(O...

Embodiment 1

[0195] Preparation of compound (4S, 5S)-4-((S)-1-acetamido-3-methylbutyl)-5-amino-1-cyclohexenecarboxylic acid

[0196]

[0197] Step A: (S,E)-6-Methyl-4-tert-butoxycarbonylamino-2-heptenal

[0198]

[0199] L-leucinol (1.29 g, 11.0 mmol) was dissolved in methanol (50 ml), and Boc anhydride (or di-tert-butyl dicarbonate, 2.64 g, 12.1 mmol) in methanol ( 10 ml) solution, stirred at room temperature for 14 hours. Rotary evaporation under reduced pressure until the solvent was evaporated to dryness, dichloromethane (30 ml) was added and washed with saturated sodium bicarbonate solution (3×20 ml), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give Color transparent liquid (2.27 g). Under nitrogen protection, oxalyl chloride (2.00 g, 15.7 mmol) was dissolved in dichloromethane (25 ml), and after cooling to -78 ° C, DMSO (2.45 g, 31.4 mmol) was added dropwise in dichloromethane (5 mL) solution...

Embodiment 2

[0213] Preparation of compound (4R, 5R)-4-((S)-1-acetamido-3-methylbutyl)-5-amino-1-cyclohexene diammonium phosphonate

[0214]

[0215] Step A: (S,E)-6-Methyl-4-tert-butoxycarbonylamino-2-heptenal

[0216]

[0217] The title compound was prepared according to the procedure described in Example 1, Step A.

[0218] Step B: Tetraethyl 3-nitropropyl-1,1-diphosphonate

[0219]

[0220] Tetraethyl methylene diphosphonate (11.7 g, 40.7 mmol) was dissolved in anhydrous methanol (100 mL), and paraformaldehyde (6.1 g, 203.5 mmol) and diethylamine (4.2 mL, 40.7 mmol), heated to reflux for 24 hours, and the solvent was evaporated to dryness by rotary evaporation under reduced pressure to obtain 12.3 grams of yellow liquid. The yellow liquid (12.3 g) was dissolved in toluene (100 ml), p-toluenesulfonic acid (344 mg, 2.0 mmol) was added, and heated to reflux in a water trap for 24 hours. The solvent was removed under reduced pressure, and the fraction with a boiling point of 10...

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Abstract

The invention provides a compound expressed by a general formula I, or its pharmaceutically acceptable salt, and an analyzed enantiomer and a purified diastereomer, wherein R<1>is H or C1-12 alkyl groups; R<2> is H, -C(O)R<1a>, -C(O)OR<1a> or -S(O)2R<1b>, wherein R<1a> is H or C1-6 alkyl groups, R<1b> is selected from H or C1-6 alkyl groups halogenated hydrocarbon, phenyl or aryl group; R<3> is selected from C1-4 alkyl groups substituted amino, halogen, hydroxyl, sulfydryl, guanidyl, nitryl or cyano group; and R<4> is -(CH2)nCO2H, -(CH2)nP(O)(OH)2, -(CH2)nCO2R<1a> and -(CH2)nP(O)(OR<1a>)2, wherein R<1a> is H or C1-6 alkyl groups, n is an integer between 0 and 4, or a salt of the above groups. The invention also provides a preparation method of the cyclohexene compound expressed by the general formula I, and an application of the cyclohexene compound taken as an influenza virus neuraminidase inhibitor for preparing the medicines to prevent or treat the influenza diseases.

Description

technical field [0001] The present invention relates to a new class of cyclohexene compounds, or pharmaceutically acceptable salts of such compounds, their preparation methods, and their application as influenza virus neuraminidase inhibitors to prevent or treat influenza diseases. Background technique [0002] Influenza is a global infectious disease caused by influenza virus, which has seriously affected the normal life of human beings and posed a great threat to the stability of human society. [0003] At present, the main method for preventing and treating influenza virus is to use neuraminidase inhibitor drugs, which target neuraminidase (NA) on the surface of influenza virus. Neuraminidase is a mushroom-shaped tetrameric glycoprotein, which plays an important role in the process of influenza virus replication and separation from host cells. When the influenza virus enters the host cell through hemagglutinin and replicates, the hemagglutinin on the surface of the matur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C231/12C07C279/16C07C277/08C07C255/45C07C253/30C07C323/61C07C319/12C07C271/24C07C269/06C07C311/20C07C303/40C07C309/30C07C303/32C07F9/44C07F9/40A61K31/664A61K31/662A61K31/277A61K31/27A61K31/245A61K31/19A61P31/16
Inventor 鲁桂黎逢权李勇波翁江
Owner SUN YAT SEN UNIV
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