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Thiazolidine neuraminidase inhibitor and application thereof

A technology of thiazolidine acids and compounds, which is applied in thiazolidine neuraminidase inhibitors and their application fields, can solve the urgent problems of research and development of neuraminidase inhibitors, and achieve a significant effect of inhibiting neuraminidase activity in vitro

Inactive Publication Date: 2011-08-10
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, two existing neuraminidase inhibitors, zanamivir and oseltamivir, have had serious side effects and drug resistance, so the research and development of new neuraminidase inhibitors is urgent

Method used

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  • Thiazolidine neuraminidase inhibitor and application thereof
  • Thiazolidine neuraminidase inhibitor and application thereof
  • Thiazolidine neuraminidase inhibitor and application thereof

Examples

Experimental program
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preparation example Construction

[0053] The preparation method of the compound of the above general formula I, the present invention uses cysteine ​​1 as a raw material, condenses with aldehyde 2 under alkaline conditions to form a thiazolidine intermediate 3, and then reacts with chloroacetyl chloride or phenylacetyl chloride in alkaline Condensation under the conditions to obtain the target compound (4) or (9), respectively; Compound (4) is further subjected to ammoniation, Boc protection and deprotection to obtain the target compound (14).

[0054] Taking o-vanillin (o-hydroxy-m-methoxybenzaldehyde) as an example below, the synthetic route and preparation method of this type of compound are illustrated.

[0055] synthetic route:

[0056]

[0057] Reagents: a. Sodium bicarbonate, ethanol / water; b. Chloroacetyl chloride, sodium bicarbonate / water; c. Phenylacetyl chloride, sodium bicarbonate / water; d. Ammonia; 2 O), sodium bicarbonate, tetrahydrofuran; ethyl acetate saturated with hydrogen chloride.

[0...

Embodiment 1

[0075] Example 1. Preparation of intermediate (2RS, 4R)-2-(2-hydroxyl-3-methoxyphenyl)-thiazolidine-4-carboxylic acid (1)

[0076] Dissolve 12.1g (0.11mol) of o-vanillin in 200mL of ethanol, and add 15.7g (0.1mol) of L-cysteine ​​hydrochloride and 11.7g (0.11mol) of sodium bicarbonate into 200mL of aqueous solution under vigorous stirring . Stir at room temperature for 6h. Stand still, filter, the precipitate is washed with ethanol and water, and after drying, 23 g of the product is obtained, the yield is 92%, and the mp is 137-138°C. 1 H-NMR (DMSO-d 6 , 300MHz): 2.931-3.040(m, 1H, 5-H), 3.171-3.368(m, 1H, 5-H), 3.777-3.858(m, 3H, -OCH 3 ), 3.836(t, 0.46H, 4-H), 4.207(t, J=5.4Hz, 0.54H, 4-H), 5.671(s, 0.46H, 2-H), 5.865(s, 0.54H, 2 -H), 6.704-6.971 (m, 3H). HRMS: m / z 256.0643.

Embodiment 2

[0077] Example 2.3-Chloroacetyl-(2RS, 4R)-2-(2-hydroxy-3-methoxyphenyl)-thiazolidine-4-carboxylic acid (4)

[0078] Intermediate (2RS, 4R)-2-(2-hydroxyl-3-methoxyphenyl)-thiazolidine-4-carboxylic acid 2.6g (0.01mol) and sodium bicarbonate 2.1g (0.02 mmol) was dissolved in 100 mL of water, 0.9 mL (0.011 mmol) of chloroacetyl chloride was added dropwise under ice-bath conditions, and the reaction was stirred for 4 h. Use sodium bicarbonate to adjust the pH of the reaction solution to 8-9, wash with dichloromethane 3 times, each dosage 50mL (50mL×3), the aqueous phase is adjusted to pH 2-3 with citric acid, dichloromethane extracted 3 times each dosage 50mL (50mL×3), combined the organic phases, dried, evaporated to dryness, purified by column chromatography to obtain 2g of the final product, yield 60.4%, mp 130-132°C, 1 H-NMR (CDCl 3 , 300MHz): 3.325-3.464 (m, 2H, 5-H), 3.773-3.818 (d, 1H, J=13.5Hz, Cl-CH 2 -), 3.916(s, 3H, -OCH 3 ), 4.010-4.055(d, 1H, J=13.5Hz, Cl-CH2-), 5....

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Abstract

The invention relates to a thiazolidine neuraminidase inhibitor and application thereof. The thiazolidine neuraminidase inhibitor is a compound shown as a formula I and a mixture of an optical isomer, a diastereoisomer and raceme of the compound. The application of the compound shown as the formula I in preparing medicines for preventing or treating diseases related to the activity of neuraminidase is disclosed.

Description

technical field [0001] The present invention relates to a class of neuraminidase-inhibiting compound with thiazolidine skeleton, preparation method and application thereof, activity test of said compound, composition containing said compound and application of these compositions. Background technique [0002] Neuraminidase (NA) is sialidase, and its enzymatic code is EC 3.2.1.18. It is a glycoprotein present on the surface of A and B influenza viruses and plays a key role in the replication and infection of influenza viruses ( Calfee, D.P.; Hayden, F.G. Drugs, 1998, 56, 537.). Neuraminidase can catalyze the cleavage of α-glycosidic bonds between sialic acid residues at the end of host cell surface receptors and glycoproteins, glycolipids, and oligosaccharides, thereby promoting the separation of newly formed virions from the sialic acid residues of host cells. The release of bases promotes the spread of virus particles from the infected respiratory mucosa to surrounding tis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/06C07D407/04A61K31/427A61K31/426A61P31/16
Inventor 徐文方刘瑜方浩
Owner SHANDONG UNIV
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