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Dinucleotide prodrug

A technology of dinucleosides and precursor compounds, which can be applied to sugar derivatives, pharmaceutical formulations, organic active ingredients, etc., and can solve problems such as not meeting the Lipinski standard

Inactive Publication Date: 2019-11-19
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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] The synthetic method of embodiment 1 compound BG001:

[0117]

[0118] Step 1: Preparation of intermediate NB-08

[0119] Add SM1 (50g, 0.1284mol), 500mL of dichloromethane, and Molecular sieve 50g. It was then stirred for 1 h under nitrogen protection. Trimethylsilyl trifluoromethanesulfonate (30ml, 0.1658mol) was slowly added dropwise to the reaction solution under an ice-water bath, and the reaction was refluxed for 40h after the dropwise addition was completed. The reaction solution was brown-black. After TLC monitors that the reaction is complete, it is lowered to room temperature, and triethylamine is added dropwise until neutral. After filtering, the filtrate was extracted and washed with ice water (3×300ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, stirred for 1 h, and filtered. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. Filter to obtain a dichloromethane solut...

Embodiment 2

[0145] Embodiment 2: Compound BG002 synthetic method

[0146]

[0147] Step 1: Preparation of intermediate NB-08

[0148] Add SM1 (50g, 0.1284mol), 500mL of dichloromethane, and Molecular sieve 50g. It was then stirred for 1 h under nitrogen protection. Trimethylsilyl trifluoromethanesulfonate (30ml, 0.1658mol) was slowly added dropwise to the reaction solution under an ice-water bath, and the reaction was refluxed for 40h after the dropwise addition was completed. The reaction solution was brown-black. After TLC monitors that the reaction is complete, it is lowered to room temperature, and triethylamine is added dropwise until neutral. After filtering, the filtrate was extracted and washed with ice water (3×300ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, stirred for 1 h, and filtered. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. Filter to obtain a dichloromethane solution of N...

Embodiment 3

[0169] The preparation of embodiment 3 compound BG003

[0170]

[0171]

[0172] Step 1: Preparation of intermediate NB-08

[0173] Add SM1 (50g, 0.1284mol), 500mL of dichloromethane, and Molecular sieve 50g. It was then stirred for 1 h under nitrogen protection. Trimethylsilyl trifluoromethanesulfonate (30ml, 0.1658mol) was slowly added dropwise to the reaction solution under an ice-water bath, and the reaction was refluxed for 40h after the dropwise addition was completed. The reaction solution was brown-black. After TLC monitors that the reaction is complete, it is lowered to room temperature, and triethylamine is added dropwise until neutral. After filtering, the filtrate was extracted and washed with ice water (3×300ml), and the aqueous layer was discarded. The organic layer was dried over anhydrous sodium sulfate, stirred for 1 h, and filtered. The filtrate was stirred and dried with anhydrous sodium sulfate for 1-2 hours. Filter to obtain a dichloromethane...

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Abstract

The invention provides a dinucleotide prodrug being novel in structure, and further provides a preparation method of a dinucleotide prodrug, and an application of the dinucleotide prodrug to preparation of drugs for treating viral infection, particularly to drugs for treating hepatitis B virus (HBV) infection and HBV relevant liver diseases. The dinucleotide prodrug compound can notably improve the target properties in the liver, can improve the accumulation capacity in liver locations, can further effectively improve the drug effect and activity, can reduce the use dosage, and can further reduce the toxic and side effects. Experimentation on animals indicates that after being absorbed in bodies, the dinucleotide prodrug compound can be rapidly distributed in extravascular tissue from a central compartment, and can be concentrated massively in the liver, and low dosage of the dinucleotide prodrug compound can be observed in other tissue. The dinucleotide prodrug compound provided by the invention also has the advantages of being high in biological availability when being taken orally, good in stability in the stomach, and long in life in vivo.

Description

technical field [0001] The invention relates to a dinucleotide prodrug with novel structure. It also relates to the preparation method of the dinucleotide prodrug 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 such as cirrhosis and hepatocellular carcinoma. A la...

Claims

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Application Information

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IPC IPC(8): C07H19/207A61K31/7084A61P31/20A61P31/14
CPCC07H19/207A61P31/20A61P31/14
Inventor 袁建栋刘平林祥义孙占莉丁海峰王叶亭
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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