Compound containing dinucleotide structure

A compound and selected technology, applied in the field of compounds containing dinucleotide structures, can solve problems such as not meeting the Lipinski standard

Active Publication Date: 2020-08-04
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In fact, dinucleotide prodrugs are compounds with relatively high molecular weight and therefore in many respects do not meet the Lipinski criteria for buccal absorption

Method used

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  • Compound containing dinucleotide structure
  • Compound containing dinucleotide structure
  • Compound containing dinucleotide structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] The synthetic method of embodiment 1 compound BG002:

[0111]

[0112] Under nitrogen protection, in the reaction flask, SM3 (4.5g, 7.7mmol), DMF (100ml), diisopropylethylamine (1.1g, 8.5mmol), sodium iodide (0.58g, 5.8mmol), 4 -Chloromethyl-5-methyl-1,3-dioxol-2-one (1.2g, 8.4mmol), after the addition was completed, the reaction was stirred at room temperature overnight, and the reaction solution was purified by column chromatography to obtain BG002 2.0g, purity 98.08%, yield 57.3%.

[0113] MS Calcd: 699; MS Found: 700 [M+H] + .

[0114] 1 H-NMR (DMSO-d 6 ,400Hz):

[0115] δ2.0177-2.0411(d,3H); 2.3059-2.3700(m,1H); 2.8201-2.9104(m,1H); 3.33(s,3H); 3.5887(s,2H); ); 4.0326-4.1349(m,3H); 4.1831-4.2859(m,1H); 4.3294-4.4024(m,1H); (t,1H);5.5369-5.5509(dd,1H);5.7020-5.7325(m,1H);5.8897-5.9135(m,1H);6.3617-6.3993(m,1H);7.2728(s,2H);7.8637 -7.8938 (m, 1H); 8.1423 (s, 1H); 8.2848-8.2965 (d, 1H); 11.4335 (s, 1H).

[0116] 13 C-NMR (DMSO-d 6 ,400Hz):

[0117] δ9.1...

Embodiment 2

[0129] The synthetic method of embodiment 2 compound BG004:

[0130]

[0131]

[0132] (1) Preparation of BG004-03:

[0133] N 2 protection, at 0°C, add acetonitrile (420ml), BG004-02 (12.0g, 51.3mmol), p-toluenesulfonyl azide (12.3g, 51.3mmol) to the reaction flask in sequence, and then add triethylamine (21.4ml, 15.4 mmol), maintained at 0°C, stirred for 30 min, and then reacted at room temperature for 4 h. The reaction solution was concentrated to dryness under reduced pressure, and slurried with 150ml×2 diethyl ether / petroleum ether=2:1 mixed reagent. Suction. The filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography with ethyl acetate / n-hexane mixed solvent to obtain 12.79 g of oily substance BG004-03 with a yield of 96%.

[0134] (2) Preparation of BG004-04:

[0135] Add tetrahydrofuran (250ml), purified water (120ml), BG004-03 (12.7g, 48.7mmol), Rh(OAc) 4 (165mg, 0.37mmol), reflux reaction for 5h. After the react...

Embodiment 3

[0148] The synthetic method of embodiment 3 compound BG012:

[0149]

[0150] (1) Preparation of BG012-02:

[0151] Under nitrogen protection, hydroxyacetone (21.0 g, 280 mmol) and dichloromethane (200 ml) were added to the reaction flask. The temperature was lowered to 0°C, and triphosgene (30.0 g, 110 mmol) was added. Control the temperature to ≤-8°C, and add N,N-dimethylaniline (37.0 g, 300 mmol) dropwise. Control the temperature at 0°C, stir and react for 15 minutes, and then react at room temperature for more than 2 hours. The temperature of the reaction solution was cooled to 5°C, and the solution was successively washed with ice-cold 3M dilute hydrochloric acid (40ml), water (30ml), and saturated sodium chloride (30ml). The organic layer was dried by adding anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to 1 / 2 volume, and refluxed for 3h. Afterwards, it was concentrated to dryness to obtain an oily substance, which was heated to 170° C...

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Abstract

The invention provides a compound containing a dinucleotide structure, which has a novel structure. The invention also provides a preparation method of the compound containing the dinucleotide structure, and an application of the compound in preparation of drugs for treating virus infection, especially hepatitis B virus (HBV) infection and liver diseases related to HBV. In another aspect, the invention also relates to a dinucleotide structure-containing compound with a pure optical isomer obtained by separation. The compounds containing the dinucleotide structures provided by the invention have the advantages of remarkable anti-HBV DNA activity, low dosage, high safety and the like, and also have good pharmacokinetic characteristics.

Description

technical field [0001] The invention relates to a compound containing a dinucleotide structure with a novel structure. It also relates to the preparation method of the compound containing the dinucleotide structure of the present invention, and its application in the preparation of medicines for treating viral infections, especially hepatitis B virus (HBV) infection and HBV-related liver diseases. Background technique [0002] Hepatitis B is one of the diseases with the greatest social burden in our country. At present, about 100 million people in my country are hepatitis B virus carriers, accounting for about 8%-10% of the total population in my country, and there are about 20 million people with chronic hepatitis B (inflammatory lesions have appeared in the liver). It is estimated that there are 350 million chronic HBV carriers worldwide. According to the Centers for Disease Control, approximately 3 to 7 million people die each year from infection-related complications s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H21/00C07H1/00A61P31/20A61P31/14A61P1/16A61K31/7084
CPCC07H21/00C07H1/00A61P31/20A61P31/14A61P1/16A61K31/7084C07H19/207A61K31/7076Y02P20/55
Inventor 袁建栋林祥义孙占莉刘平
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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