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Structure and synthesis of novel nucleoside phosphate prodrug containing substituted benzyl

A technology of nucleoside phosphate and phosphate, which is applied in the field of valence and can solve problems such as the inability to use antiviral drugs

Inactive Publication Date: 2013-12-11
刘沛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Nucleoside triphosphate itself has multiple negative charges and very high polarity, so it is difficult to pass through the cell wall and enter the interior of the cell, so it cannot be used directly as an antiviral drug

Method used

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  • Structure and synthesis of novel nucleoside phosphate prodrug containing substituted benzyl
  • Structure and synthesis of novel nucleoside phosphate prodrug containing substituted benzyl
  • Structure and synthesis of novel nucleoside phosphate prodrug containing substituted benzyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069]

[0070] Compound ( 9 , 12.8g, 50mmol) was dissolved in dichloromethane (100mL) and cooled to -78°C, o-methylbenzyl alcohol (6.1g, 50mmol) and triethylamine (7.7mL, 55mmol) were slowly added dropwise within 20 minutes dichloromethane (100mL) solution. The reaction was stirred at -78 °C for 30 min, then transferred to another reaction containing dry L-alanine hydrochloride (7.68 g, 50 mmol) in dichloromethane (100 mL) at 0 °C in the container. Triethylamine (14.7 mL, 105 mmol) was slowly added dropwise to the above reaction solution, and the dropwise addition was completed in 20 minutes, and the reaction solution was continuously stirred at zero temperature for one hour. The solvent was removed by rotary evaporation, ethyl acetate was added to grind powder, filtered, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:3) to obtain a colorless oily product ( 11 ) (17.7g, 84%),...

Embodiment 2

[0073]

[0074] compound ( 12 , 296 mg, 1 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and tert-butylmagnesium chloride Grignard reagent (1.0 M, 4 mL, 4 mmol) was added at room temperature. After stirring and reacting for 30 minutes, slowly add compound ( 11 , 844mg, 2mmol) in tetrahydrofuran (4mL), the reaction mixture was stirred at room temperature for 24 hours, TLC monitored that the reaction was complete, then added saturated ammonium chloride solution (20mL) to quench, extracted with ethyl acetate (20mLx3), the organic phases were combined and dried , concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a white powder product ( 13 ) (370 mg, 64%). 1 H NMR (CD 3OD, 400MHz) δ8.50(s, 0.5H), 8.47(s, 0.5H), 8.39(s, 0.5H), 8.35(s, 0.5H), 7.28-7.30(m, 1H), 7.09-7.17 (m, 3H), 6.15(s, 0.5H), 6.14(s, 0.5H), 5.04-5.09(m, 2H), 4.22-4.60(m, 4H), 4.16(s, 3H), 4.02-4.07 (m, 2H), 3.78-3.81(m, 1H), ...

Embodiment 3

[0076]

[0077] Using the same synthetic method as in Example 15, the compound ( 14 )and( 11 ) is coupled under the effect of tert-butylmagnesium chloride Grignard reagent to obtain a white powdery product ( 15 ). 1 H NMR (CD 3 OD, 400MHz) δ7.93(s, 0.5H), 7.90(s, 0.5H), 7.28-7.31(m, 1H), 7.10-7.17(m, 3H), 5.95(s, 0.5H), 5.94( s, 0.5H), 5.04-5.09(m, 2H), 4.00-4.43(m, 6H), 4.02(s, 3H), 3.78-3.82(m, 1H), 2.27-2.31(m, 3H), 1.27 -1.31(m, 3H), 1.13-1.16(m, 3H), 0.90-0.95(m, 3H); 31 P NMR (CD 3 OD) δ 9.76, 9.67; MS (m / z) 595 (M+H).

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Abstract

The invention describes a phosphate structure containing substituted benzyl, wherein the phosphate structure is shown as a formula (I) and a formula (II). The phosphate structure can be used as prodrugs for various nucleoside analogues including non-cyclic nucleoside, carbon-cyclic nucleoside, furan-cyclic nucleoside and the like, and enhance bioactivity of nucleoside compounds, and thus the structure can be applied in treatment for virus infections and cancers.

Description

technical field [0001] The present invention relates to a new class of substituted benzyl-containing nucleoside analog phosphate prodrugs (I) and (II), and their isomers or pharmaceutically acceptable salts, as the equivalent of nucleoside monophosphate, it structural features and their preparation methods. [0002] Background of the invention [0003] Nucleoside compounds are deoxyribonucleic acid and ribonucleic acid, that is, the structural monomers of biological genetic genes DNA and RNA, so they have important functions in all living organisms and are widely used in the treatment of viral infections and cancer. Since the 1960s, many biologically active nucleoside analogs have been used to treat various viral infections such as herpes, AIDS, and hepatitis B and C. These artificially synthesized nucleoside analogs can block the growth of viral nucleic acid chains, destroy the replication of viral genes, and become antiviral drugs ( figure 1 ). [0004] [0005] l...

Claims

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Application Information

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IPC IPC(8): C07H19/207C07H19/10C07H1/02C07F9/6561A61K31/7076A61K31/7072A61K31/685A61P31/14A61P31/18A61P31/20A61P35/00
Inventor 刘沛
Owner 刘沛
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