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Cyclohexene derivative or pharmaceutically acceptable salt thereof and application of cyclohexene derivative and salt

A technology of cyclohexene and derivatives, applied in the field of medicine, can solve problems such as difficult to meet clinical needs, increase dosage, and decrease activity, and achieve the effects of meeting the needs of clinical applications, improving stability, and good inhibitory effect

Active Publication Date: 2017-11-07
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the Tamiflu resistance caused by the H274Y mutation, its activity has been reduced by more than 300 times, and it is difficult to increase the dose to meet the clinical needs
The recently approved peramivir is also only marginally effective against the H274Y mutant influenza virus

Method used

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  • Cyclohexene derivative or pharmaceutically acceptable salt thereof and application of cyclohexene derivative and salt
  • Cyclohexene derivative or pharmaceutically acceptable salt thereof and application of cyclohexene derivative and salt
  • Cyclohexene derivative or pharmaceutically acceptable salt thereof and application of cyclohexene derivative and salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of (3R,4R,5S)-4-acetamido-5-guanidino-3-((3R)-3-n-butanesulfonamidopiperidine)-1-cyclohexene-1-carboxylic acid.

[0055] a) (3R,4S,5S)-4-acetamido-5-azido-3-((3R)-3-n-butylsulfonamide piperidine)-1-cyclohexene-1-carboxylic acid ethyl Preparation of esters.

[0056]

[0057] Preparation of (3R,4R,5S)-4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester: See J.Am.Chem.Soc for the preparation method ., 1997(119):681-690.

[0058] Place 20mmol of (3R,4R,5S)-4-acetamido-5-azido-3-acetoxy-1-cyclohexene-1-carboxylic acid ethyl ester and 1mmol of tetrakistriphenylphosphine palladium in In a dry two-necked flask, replace the air in the system twice with nitrogen, add 40mL redistilled DMF with a syringe and stir evenly, add 40mmol DIPEA (N,N-diisopropylethylamine) and stir to cool to 0°C , slowly add (R)-3-n-butylsulfonamidopiperidine trifluoroacetate DMF (40mL) solution dropwise, continue to stir at 0°C for 20 minutes after the addition, tr...

Embodiment 2

[0088] 1. Determination of Influenza Virus Neuraminidase Activity

[0089] Experimental materials: NA enzyme (neuraminidase) liquid: the allantoic fluid of chicken embryos infected with influenza virus

[0090] Enzymatic reaction system: 330mmol / L MES buffer (pH3.5)

[0091] 200μmol / L fluorescent substrate MUNANA

[0092] 4mmol / L CaCl 2 the solution

[0093] Stop solution: 14mmol / L NaOH solution (14mmol / L, 83% ethanol)

[0094] Oseltamivir: 1mmol / L

[0095] Peramivir: 1mmol / L

[0096] Reference compound: the following compound of formula II, 1mmol / L

[0097]

[0098] Enzyme activity assay:

[0099]

[0100] EX=355nmXM=460nm

[0101] Note: In order to verify whether the enzyme reaction system is normal, the kinetic curve of the fluorescence value can be measured without adding stop solution.

[0102] NA inhibitor screening experiment operation:

[0103] 1. Dilute oseltamivir, peramivir or the test compound (compound of formula I, II) at 1:10, 1:100, 1:1000, 1:10...

Embodiment 3

[0142] 1. Solubility experiments of different salts of the compound of formula I.

[0143] Adopt different acids such as lactic acid, hydrochloric acid, phosphoric acid, acetic acid, malic acid, citric acid, aspartic acid and formula I compound salt-forming reaction, investigate the solubility of the different salts of formula I compound, the results are shown in the table below.

[0144] Table 3. Solubility of different salts of compounds of formula I

[0145] compound type

[0146] As can be seen from the above results, the solubility of the compound of formula I after salting with acids such as lactic acid, hydrochloric acid, phosphoric acid, acetic acid, malic acid, citric acid, and aspartic acid all increases significantly, and most of them are under the condition of pH=3.8. The solubility is greater than 100mg / mL, and when the molar ratio with lactic acid is about 1:2, the solubility of salt formation reaches 194mg / mL, and the pH of the solution is 3.8; when th...

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Abstract

The invention relates to a cyclohexene derivative or pharmaceutically acceptable salt thereof and an application of the cyclohexene derivative and salt, and belongs to the technical field of a medicine. The cyclohexene derivative or pharmaceutically acceptable salt thereof shown in the formula I is a new broad-spectrum anti-influenza compound, has a better inhibition effect on influenza virus, particularly has high activity to oseltamivir-resistant virus strains, and can be used as a wide-spectrum anti-influenza neuraminidase inhibitor which is effective to tamiflu resistance and has broad spectrum. The cyclohexene derivative or pharmaceutically acceptable salt can be used for treating influenza caused by influenza virus and is a new broad-spectrum anti-influenza drug.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a cyclohexene derivative or a pharmaceutically acceptable salt thereof and its application. Background technique [0002] Influenza is an acute viral respiratory infectious disease caused by influenza virus that seriously endangers human health. At present, the control and treatment of influenza in China mainly use antipyretic, analgesic and cough medicine for symptomatic treatment, or inoculation of inactivated vaccine for prevention. Some countries use amantadine and rimantadine to prevent and treat type A influenza, but both amantadine and rimantadine are ineffective against type B influenza, and long-term use of amantadine has many adverse reactions. Amantadine is no longer recommended for the treatment of influenza in many countries. Due to the variation of influenza virus antigens, conventional vaccines cannot effectively prevent influenza outbreaks and epidemics. Theref...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56A61K31/451A61K9/19A61P31/16
CPCC07D211/56A61K9/0019A61K9/19A61K31/451A61P31/16A61J3/02A61K47/02A61K47/12A61K47/26
Inventor 张健存李德耀李宏王坤刘燕吴妍唐星宋健波
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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