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Acyclic nucleoside cyclic phosphate derivatives, preparation method and medical application thereof

A pharmaceutical and aromatic ring technology, applied in the field of preparation of antiviral drugs, can solve the problems of nephrotoxicity, highly sensitive hydrolysis reaction, no phase 3 clinical reports, etc., and achieve the effect of reducing toxic and side effects

Inactive Publication Date: 2016-08-03
李勤耕
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 PieterAnnaert , PharmaceuticalResearch.1997,14(4):492-496.); (2) there is certain nephrotoxicity when used in high doses, mainly manifested as the increase of serum creatinine and the decrease of blood phosphorus; (3) long-term use of Adelaide When fovir dipivoxil is used, pivalic acid released by hydrolysis may reduce carnitine in serum (see Jae-TaegHwang.DrugsoftheFuture2004,29(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 phosphate derivatives, preparation method and medical application thereof
  • Acyclic nucleoside cyclic phosphate derivatives, preparation method and medical application thereof
  • Acyclic nucleoside cyclic phosphate derivatives, preparation method and medical application thereof

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, suspend PMEA (3.00g, 10.99mmol) in dry dichloromethane (40ml), then add N,N-diethylformamide (1.35ml, 12.12mmol), stir, and slowly add oxalyl chloride dropwise (3.5ml, 36.80mmol), after the dropwise addition, heat and reflux for 2 hours, cool to room temperature, concentrate under reduced pressure, add dry dichloromethane (40ml) to the residue, dissolve and then concentrate under reduced pressure, then add dry dichloromethane (40ml), slowly added pyridine (1.08ml, 13.42mmol) under ice-bath conditions and stored under these conditions for later use.

[0039] 2-Phenyl-1,3-propanediol (1.672g, 10.97mmol), triethylamine (7.5ml, 53.96mmol), dissolved in dry dichloromethane (30ml), liquid nitrogen-acetone bath, the reaction solution was cooled to -78°C, then slowly add the above standby solution dropwise, and control the temper...

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 reacted as raw materials to generate compound 2, the product weighed 2.29g, and the total yield was 44.8%. MS(ESI), foundm / z466, 488, calcd466[M+H] + , 488[M+Na] + . 1 HNMR (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 reacted as raw materials to generate compound 3, the product weighed 1.57g, and the total yield was 34.1 %. MS(ESI), foundm / z420, 442, calcd420[M+H] + , 442[M+Na] + . 1 HNMR (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 invention relates to the fields of medicinal chemistry, drug synthesis and pharmacology, more specifically, a series of acyclic nucleoside cyclic phosphate derivatives and their composition, preparation method and application in the preparation of antiviral drugs. Background technique [0002] Hepatitis B virus (HepatitisB, HB), referred to as hepatitis B, is a disease that seriously endangers human health caused by hepatitis B virus (hepatitisBvirus, HBV). Features. According to the statistics of the World Health Organization (WHO), there are approximately 2 billion HBV-infected persons in the world, of which 350 million are chronically infected with HBV. Chronic HBV infection can then cause chronic hepatitis B (chronichepatitisB, CHB) and liver cirrhosis LC) and primary hepatocellular carcinoma (hepatocellular carcinoma, HCC) and other related diseases, about 1 million people worldwide die from hepatitis B-related liver diseases every year. my ...

Claims

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Application Information

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Patent Type & Authority Patents(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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