Acyclic nucleoside cyclic phosphonate derivative, its preparation and use

A drug and aromatic ring technology, applied in the field of preparing antiviral drugs, can solve the problems of elevated serum creatinine, nephrotoxicity, high sensitivity to hydrolysis reaction, etc., and achieve the effect of reducing toxic and side effects

Inactive Publication Date: 2013-01-02
李勤耕
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the drug also has the following defects in its application: (1) it is highly sensitive to the hydrolysis reaction mediated by serum, and can be distributed in most tissues, wherein the intestine, liver, and kidney have the highest concentration, and cannot effectively increase the drug concentration at the site of action (see Pieter Annaert, Pharmaceutical Research.1997,14(4):492-496.); (2) There is a certain degree of nephrotoxicity when used in high doses, mainly manifested as an increase in serum creatinine and a decrease in blood phosphorus; (3) Long-term use When adefovir dipivoxil is used, pivalic acid released by hydrolysis may reduce carnitine in serum (see Jae-Taeg Hwang. Drugs of the Future 2004,29(2);163-177)
Pradefovir, one of the prodrugs, ended Phase 2 clinical trials in 2006, and was originally planned to enter Phase 3 clinical trials in 2007, but there has been no report of entering Phase 3 clinical trials so far.

Method used

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  • Acyclic nucleoside cyclic phosphonate derivative, its preparation and use
  • Acyclic nucleoside cyclic phosphonate derivative, its preparation and use
  • Acyclic nucleoside cyclic phosphonate derivative, its preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of 9-[2-(2-phenyl)-2-oxa-1,3,2-dioxaphosphorylhexyl-2-methyleneoxyethyl]adenine (Compound 1).

[0037]

[0038] N 2 Under protection, PMEA (3.00g, 10.99mmol) was suspended in dry dichloromethane (40ml), then N,N-diethylformamide (1.35ml, 12.12mmol) was added, stirred, and oxalyl chloride was slowly added dropwise (3.5ml, 36.80mmol). After the addition is complete, warm to reflux for 2 hours, cool to room temperature, concentrate under reduced pressure, add dry dichloromethane (40ml) to the residue, dissolve, concentrate under reduced pressure, and add dry Dichloromethane (40ml), slowly add pyridine (1.08ml, 13.42mmol) under ice bath conditions and store under these conditions for later use.

[0039] Dissolve 2-phenyl-1,3-propanediol (1.672g, 10.97mmol) and triethylamine (7.5ml, 53.96mmol) in dry dichloromethane (30ml) in a liquid nitrogen-acetone bath, and cool the reaction solution To -78°C, then slowly add the above standby solution dropwise. During the dropwi...

Embodiment 2

[0042] 9-[2-(1,3-Diphenyl)-2-oxa-1,3,2-dioxaphosphorylhexyl-2-methyleneoxyethyl]adenine (compound 2) preparation.

[0043]

[0044] According to the operation of Example 1, PMEA (3.00g, 10.99mmol) and 1,3-diphenylpropanediol (2.51g, 10.99mmol) were used as raw materials to react to produce compound 2. The product weighed 2.29g and the total yield was 44.8%. MS (ESI), found m / z 466, 488, calcd 466[M+H] + , 488[M+Na] + . 1 H NMR(CDCl 3 ): δ=2.10-2.52 (m, 2H), 3.88-4.14 (m, 4H), 4.28-4.59 (t, 2H), 5.42-5.85 (m, 2H), 6.29-6.85 (s, 2H), 7.10 -7.25 (m, 2H), 7.28-7.50 (m, 8H), 7.80-8.02 (s, 1H), 8.11-8.35 (s, 1H). IR (KBr): 3328, 3162, 1659, 1597, 1247, 1052.

Embodiment 3

[0046] Preparation of 9-[2-(2-benzyloxy)-2-oxa-1,3,2-dioxaphosphorylhexyl-2-methyleneoxyethyl]adenine (Compound 3).

[0047]

[0048] According to the operation of Example 1, PMEA (3.00g, 10.99mmol) and 2-benzyloxy-1,3-propanediol (2.00g, 10.99mmol) were used as raw materials to react to produce compound 3. The product weighs 1.57g and the total yield is 34.1 %. MS (ESI), found m / z 420, 442, calcd 420[M+H] + , 442[M+Na] + . 1 H NMR(CDCl 3 ): δ=3.44-3.52(m, 1H), 3.92-3.98(m, 4H), 4.12-4.37(m, 4H), 4.38-4.45(t, 2H), 4.57-4.64(s, 2H), 5.68 -6.00 (s, 2H), 7.30-7.41 (m, 5H), 7.83-7.94 (s, 1H), 8.28-8.37 (s, 1H). IR (KBr): 3345, 3168, 1650, 1597, 1251, 1048.

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Abstract

The invention relates to the field of pharmaceutical chemistry, specifically, the invention relates to a type of purine compounds with structure shown in structural formula (I) and its pharmaceutically-acceptable inorganic or organic salt crystal hydrate and solvate capable of treating hepatitis B, and its preparation method and use, and composition containing the compound. The inventive purine compounds have strong antiviral activity, and are especially suitable for treating hepatitis B.

Description

Technical field [0001] The present invention relates to the fields of medicinal chemistry, drug synthesis and pharmacology, and more specifically to a series of non-cyclic nucleoside cyclic phosphate derivatives and their compositions, preparation methods and applications in the preparation of antiviral drugs. Background technique [0002] Hepatitis B (HB), abbreviated as hepatitis B, is a disease caused by hepatitis B virus (HBV) that seriously endangers human health. It is highly infectious and has a high incidence of disease. Harmful and other characteristics. According to statistics from the World Health Organization (WHO), there are approximately 2 billion HBV infected people in the world, of which 350 million are chronically infected with HBV. Chronic HBV infection can then cause chronic hepatitis B (CHB) and liver cirrhosis ( 1iver cirrhosis (LC) and primary hepatocellular carcinoma (hepatocellular carcinoma, HCC) and other related diseases. Approximately 1 million people...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6574A61K31/675A61P31/12A61P31/20A61P1/16A61P31/18
CPCY02P20/55
Inventor 李勤耕沈宜郭彬
Owner 李勤耕
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