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Sialic acid analogues or pharmaceutically acceptable salts and application thereof

A technology of analogs and sialic acid, applied in the field of sialic acid analogs or their pharmaceutically acceptable salts and their applications, can solve the problems of poor oral bioavailability, rapid excretion, etc., achieve superior application prospects, and inhibit influenza virus , good inhibitory effect

Inactive Publication Date: 2015-11-25
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the existing neuraminidase inhibitors have the following disadvantages: oral bioavailability is poor and they are easily excreted quickly, so they can only be inhaled through the nasal cavity or breath in clinical practice; the common adverse reactions are nasopharyngeal discomfort, nausea and diarrhea , headache, cough, dizziness, epistaxis, etc.

Method used

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  • Sialic acid analogues or pharmaceutically acceptable salts and application thereof
  • Sialic acid analogues or pharmaceutically acceptable salts and application thereof
  • Sialic acid analogues or pharmaceutically acceptable salts and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The preparation of compound 17a comprises the following steps:

[0067] (1) Preparation of compound 2.

[0068] Add 5 g of cesium carbonate to 10 ml of aqueous solution of sialic acid 1 (10 g, 32.4 mmol), adjust the pH value to 7-8, spin the solvent under reduced pressure, add 30 mL of DMF and 6 mL of benzyl bromide, react at room temperature for 24 hours, suction filter, and the filtrate Pour it into 1000mL of dichloromethane, a lot of solids precipitate out, and filter it with suction to obtain compound 2.

[0069] The characterization data of this compound 2 is: 1HNMR (400MHz, D 2 O,ppm)δ7.31-7.41(m,5H),5.22(dd,J=22.4,12.8Hz,2H),4.04(m,1H),3.99(dd,J=10.4,1.6Hz,1H), 3.80(d,J=2.8Hz,1H),3.77(m,1H),3.70(m,1H),3.62(dd,J=10.8,5.2Hz,1H),3.48(dd,J=9.2,1.2Hz ,1H),2.22(dd,J=12.8,5.2Hz,1H),1.91(dd,J=12.8,11.2Hz,1H); LC-MSm / z398[M+H] + .

[0070] (2) Preparation of Compound 3.

[0071] Dissolve 0.31 mol of compound 2 in pyridine (250 mL, 3.1 mol), add a catalytic amount of...

Embodiment 2

[0102] The preparation of compound 17b, compound 17b was prepared by the method for preparing compound 17a in Example 1, wherein, after obtaining compound 8 in Example 1, the following steps were performed:

[0103] (8) Preparation of Compound 9b.

[0104] Compound 8 (0.2mmol), EDCI (0.3mmol), Et 3 N (0.3 mmol) was dissolved in 5 mL of dichloromethane, an equivalent amount of glycine was added, and stirred at room temperature for 24 h. After TLC showed that compound 8 disappeared, dichloromethane was removed by rotary evaporation under reduced pressure, and compound 9b was obtained by column chromatography.

[0105] (9) Preparation of compound 10b: same as compound 10a, except that compound 9a is replaced by compound 9b.

[0106] (10) Preparation of compound 11b: Same as compound 11a, except that compound 10a is replaced by compound 10b.

[0107] (11) Preparation of compound 13b: Same as compound 13a, except that N-(3-aminopropyl)-3,4-dihydroxybenzamide is replaced by N-(3-a...

Embodiment 3

[0112] For the preparation of compound 17c, compound 17c was prepared by the method for preparing compound 17a in Example 1, wherein, after obtaining compound 8, the following steps were performed:

[0113] (8) Preparation of Compound 9c.

[0114] Dissolve compound 8 (0.2mmol), EDCI (0.3mmol), Et3N (0.3mmol) in 5mL of dichloromethane, add an equivalent amount of aminoisopropionic acid, stir at room temperature for 24h, after TLC shows that the starting material 8 disappears, spin down under reduced pressure Dichloromethane was distilled off and further purified by column chromatography to obtain compound 9c.

[0115] (9) Preparation of compound 10c: same as compound 10a, except that compound 9a is replaced by compound 9c.

[0116] (10) Preparation of compound 11c: Same as compound 11a, except that compound 10a is replaced by compound 10c.

[0117] (11) Preparation of compound 13c: Same as compound 13a, except that N-(3-aminopropyl)-3,4-dihydroxybenzamide is replaced by N-(3-...

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PUM

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Abstract

The present invention discloses sialic acid analogues as shown in formula I, or pharmaceutically acceptable salts and application thereof, and belongs to the field of pharmaceutical chemistry. A series of sialic acid analogues are obtained by use of zanamivir as a lead compound for transformation of the side chain of the molecular structure, the sialic acid analogues or the pharmaceutically acceptable salts have good inhibitory activity on influenza virus neuraminidase, so that the sialic acid analogues can be used to prepare anti-influenza virus drugs.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a sialic acid analogue or a pharmaceutically acceptable salt thereof and applications thereof. Background technique [0002] Influenza is a common respiratory illness that can be debilitating, cause multiple complications, sometimes require hospital admission and can be fatal. Moreover, it is highly contagious, and people with weaker resistance to the elderly and infirm can easily infect each other, causing a certain range of epidemics. Annual influenza epidemics cause 3 to 5 million severe cases and 300,000 to 500,000 deaths. People older than 65 years old and younger than two years old with weak immune system are at high risk of serious illness and death. [0003] Influenza virus has a wide range of hosts and a segmented genome. During the process of infection and replication, it is prone to gene mutation or gene reassortment to form new variants. This is the fund...

Claims

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Application Information

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IPC IPC(8): C07D309/28C07D407/12A61K31/351A61K31/36A61P31/16
CPCC07D309/28C07D407/12
Inventor 张健存陈超南
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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