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5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity and preparation method thereof

A technology of formyl pyrimidine nucleoside compound and pyrimidine nucleoside, which is applied in the field of pyrimidine nucleoside derivatives, can solve the problems that have not been reported, and achieve the effect of simple preparation process, short synthetic route and significant anti-HIV activity

Active Publication Date: 2016-09-28
SHANGHAI HONGENE BIOENGINEERING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the structure, synthesis method and anti-HIV activity of this type of hybrid inhibitor.

Method used

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  • 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity and preparation method thereof
  • 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity and preparation method thereof
  • 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of 5-(tetrahydrothiazol-2-yl)-3'-fluoro-2', 3'-dideoxy-5'-acetoxyuridine (a)

[0026] Add 5-formyl-3'-fluoro-2', 3'-dideoxy-5'-acetoxyuridine (0.300 g, 1 mmol) and cysteamine hydrochloride in turn in the reaction flask (0.170 g, 1.5 mmol), sodium acetate (0.123 g, 1.5 mmol) and methanol (20 mL), the reaction was stirred at room temperature until the reaction was complete (TLC tracking monitoring). After methanol was removed under reduced pressure, ethyl acetate (20 mL) was added and washed with water and saturated sodium chloride solution successively. The obtained organic phase was dried with anhydrous sodium sulfate and spin-dried, and the residue was separated by column chromatography to obtain the product a (0.305 g) as a white solid with a yield of 85%.

[0027] The structural formula and structural characterization data of product a are as follows:

[0028]

[0029] Product a is a mixture of a pair of isomers, the molar ratio of the two isomers is 1...

Embodiment 2

[0031] Synthesis of 5-(4'-methoxyformyltetrahydrothiazol-2-yl)-2'-deoxy-3', 5'-diacetoxyuridine (b)

[0032] Add 5-formyl-2'-deoxy-3', 5'-bisacetoxyuridine (0.340 g, 1 mmol), cysteine ​​methyl ester hydrochloride (0.257 g , 1.5 mmol), potassium acetate (0.147 g, 1.5 mmol) and dichloromethane (20 mL), the reaction was stirred at reflux until the reaction was completed (TLC tracking monitoring). Washed with water and saturated sodium chloride solution successively, the organic phase was dried with anhydrous sodium sulfate, and spin-dried, and the residue was separated by column chromatography to obtain product b (0.430 g) as a yellow solid, with a yield of 94%.

[0033] The structural formula and structural characterization data of product b are as follows:

[0034]

[0035] Product b is a mixture of a pair of isomers, the molar ratio of the two isomers is 1:1.4. 1 H NMR (400MHz, CDCl 3 ) δ: 2.02-2.05 (m,14.4H), 2.12-2.20 (m, 2.4H), 2.38-2.20 (m, 2.4H),2.95 (t, J = 9.6 Hz,...

Embodiment 3

[0037] Synthesis of 5-(4'-ethoxyformyltetrahydrothiazol-2-yl)-3'-azido-2',3'-dideoxyuridine (c)

[0038] Add 5-formyl-3'-azido-2',3'-dideoxyuridine (0.281 g, 1 mmol), cysteine ​​ethyl ester hydrochloride (0.279 g , 1.5 mmol), sodium bicarbonate (0.126 g, 1.5 mmol) and dichloromethane (20 mL), the reaction was stirred at room temperature until the reaction was completed (TLC tracking monitoring). Washed with water and saturated sodium chloride solution successively, the organic phase was dried with anhydrous sodium sulfate, and spin-dried, and the residue was separated by column chromatography to obtain product c (0.326 g) as a yellow solid with a yield of 79%.

[0039] The structural formula and structural characterization data of product c are as follows:

[0040]

[0041] Product c is a mixture of a pair of isomers, the molar ratio of the two isomers is 1:1. 1 H NMR (400MHz, CDCl 3 ) δ: 1.19-1.24 (m, 6H), 2.38 (br s, 4H), 2.93-2.98 (m, 1H), 3.02-3.06 (m, 1H), 3.21-3.30...

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Abstract

The invention discloses a 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity and a preparation method thereof. The main points of the technical scheme of the present invention are: a 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity, which has the following structure: . The invention also discloses a preparation method of the 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid and a pharmaceutical composition with anti-HIV activity. The 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid provided by the present invention has significant anti-HIV activity, and contains the 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid A or its combination with a pharmaceutically acceptable acid or The pharmaceutical composition of the addition salt formed by the base can be used for the treatment of AIDS.

Description

technical field [0001] The invention relates to a class of pyrimidine nucleoside derivatives with anti-human immunodeficiency virus (HIV) activity, in particular to a 5-substituted pyrimidine nucleoside-tetrahydrothiazole hybrid with anti-HIV activity and a preparation method thereof. Background technique [0002] AIDS is an infectious disease caused by human immunodeficiency virus (HIV) infection. In the replication process of HIV, HIV reverse transcriptase (RT) plays a very important role. Therefore, designing new anti-HIV drugs targeting HIV reverse transcriptase has become one of the commonly used and very effective methods for drug development. The currently developed HIV reverse transcriptase inhibitor drugs can be divided into nucleoside inhibitors (NRTIs) and non-nucleoside inhibitors (NNRTIs) structurally. These HIV reverse transcriptase inhibitors usually have significant curative effect, but also often bring certain toxic and side effects and long-term use will ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H19/06C07H1/00A61K31/7072A61P31/18
Inventor 范学森张新迎李坤郭胜海
Owner SHANGHAI HONGENE BIOENGINEERING CO LTD
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