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Novel nucleoside phosphate prodrug containing substituted benzyl, preparation method and application thereof

A technology of medicinal salt and hydroxyl, which is applied in the field of medicine, can solve the problems of no patent report, failure to become a mononucleotide equivalent, difficulty in hydrolysis, etc., and achieve a significant effect of liver targeting

Active Publication Date: 2014-08-13
刘沛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 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
However, phosphoramidates (4-1, Figure 4 ) but mostly cannot become the equivalent of its single nucleotide, and there is no relevant patent report
The reason is that the phosphoester bond P-O-R formed by the phosphorylation of fatty alcohol is difficult to hydrolyze, and the carboxylic acid derivative (4-2) released by the hydrolysis of the amino acid ester cannot be hydrolyzed to form a five-membered ring phosphate (4-3) , thereby blocking the generation of mononucleotides (4-4)

Method used

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  • Novel nucleoside phosphate prodrug containing substituted benzyl, preparation method and application thereof
  • Novel nucleoside phosphate prodrug containing substituted benzyl, preparation method and application thereof
  • Novel nucleoside phosphate prodrug containing substituted benzyl, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101]

[0102] Compound (9, 12.8g, 50mmol) was dissolved in dichloromethane (100mL) and cooled to -78°C, o-methylbenzyl alcohol (6.1g, 50mmol) and triethylamine (7.7 mL, 55mmol) in dichloromethane (100mL) solution. The reaction was stirred at -78 °C for 30 minutes, 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%), it can solidify slowly after a long tim...

Embodiment 2

[0105]

[0106] compound ( 12 , 296mg, 1mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, and tert-butylmagnesium chloride Grignard reagent (1.0M, 4mL, 4mmol) 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 (20mL x3), the organic phases were combined, Drying, concentration, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a white powder product ( 13 ) (370 mg, 64%).

[0107] 1 H NMR (CD 3 OD,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),2.31(s,1.5H),2.30(s,1.5H...

Embodiment 3

[0109]

[0110] Using the same synthetic method as in Example 2, the compound ( 14 )and( 11 ) is coupled under the effect of tert-butylmagnesium chloride Grignard reagent to obtain a white powdery product ( 15 ).

[0111] 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 relates to a novel nucleoside phosphate prodrug containing substituted benzyl, a preparation method and an application. The novel nucleoside phosphate prodrug containing substituted benzyl is a compound or its isomer or medicinal salt shown in a formula (I) or a formula (II), can be used as prodrugs for various nucleoside analogues including non-cyclic nucleoside, carbon-cyclic nucleoside, furan-cyclic nucleoside, so that biological activity of the nucleoside compound can be reinforced, and the nucleoside phosphate prodrug can be used for treating virus infection and cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a novel nucleoside phosphate prodrug containing a substituted benzyl group and its preparation method and application. Background technique [0002] 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 ). [0003] Such as figure 1 As shown, nucleosides must first be activated into nucleoside triphosphates in three steps befor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07H19/20C07H19/10A61K31/675A61K31/7076A61K31/7068A61P31/14A61P31/18A61P31/20A61P35/00
Inventor 刘沛
Owner 刘沛
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