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D-amino-acid ester-containing nucleoside amino phosphonate derivative and medical purpose thereof

An amino acid ester and phosphonate technology, applied in the field of medicine, can solve the problem of inability to use antiviral drugs, and achieve the effect of significant liver targeting effect and metabolic stability improvement.

Active Publication Date: 2016-12-07
SHENZHEN VYBIO PHARM TECH CO LTD
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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

Method used

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  • D-amino-acid ester-containing nucleoside amino phosphonate derivative and medical purpose thereof
  • D-amino-acid ester-containing nucleoside amino phosphonate derivative and medical purpose thereof
  • D-amino-acid ester-containing nucleoside amino phosphonate derivative and medical purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101]

[0102] compound ( 9 , 12.8 g, 50 mmol) was dissolved in dichloromethane (100 mL) and cooled to -78 °C, and o-methylbenzyl alcohol (6.1 g, 50 mmol) and triethylamine (7.7 mL, 55 mmol) were slowly added dropwise within 20 minutes. of dichloromethane (100 mL). The reaction solution was stirred at -78°C for 30 minutes, then warmed to 0°C, and a solution of dry D-alanine isopropyl ester hydrochloride (7.68 g, 50 mmol) in dichloromethane (100 mL) was slowly added, followed by adding the above solution to the mixture. Triethylamine (14.7 mL, 105 mmol) was slowly added dropwise to the reaction solution, and the dropwise addition was completed in 90 minutes, and the reaction solution was continuously stirred at zero temperature for 3 hours. The solvent was removed by rotary evaporation, ethyl acetate was added to powder, filtered, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:3...

Embodiment 2

[0105]

[0106] 2-Methylbenzyl alcohol (122 mg, 1 mmol) and POCl 3 A solution of (95 μL, 1 mmol) in dichloromethane (5 mL) was cooled to -78° C., and triethylamine (140 μL, 1 mmol) was slowly added dropwise, and stirring was continued for 4 hours after the dropwise addition. A solution of D-alanine isopropyl ester hydrochloride (168 mg, 1 mmol) and triethylamine (280 μL, 2 mmol) in dichloromethane (5 mL) was added dropwise to the reaction solution at -78°C, and the reaction was performed for 60 minutes. The reaction solution was gradually heated to 0°C over 1.5 hours.

[0107] A solution of pentafluorophenol (184 mg, 1 mmol) in dichloromethane (5 mL) was added to the reaction flask, then triethylamine (140 μL, 1 mmol) was slowly added dropwise within 1 hour, and the reaction solution was slowly warmed to room temperature and stirred overnight. Triethylamine hydrochloride was removed by filtration, the filter cake was washed with a small amount of dichloromethane, and the c...

Embodiment 3

[0112]

[0113] compound 14 (260 mg, 1 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, tert-butylmagnesium chloride Grignard reagent (1.0 M, 2 mL, 2 mmol) was added at 0°C, and the reaction was stirred at room temperature for 30 minutes. Slowly add the compound dropwise 11 (870 mg, 2 mmol) in tetrahydrofuran (4 mL), the reaction mixture was stirred at room temperature for 24 hours, quenched by the addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried, and concentrated , the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a white foamy product ( 15a )and( 15b ).

[0114] ( 15a ) 1 H NMR (CD 3 OD, 400MHz) δ7.54 (d, J=8.0Hz, 1H), 7.12-7.42 (m, 4H), 6.18 (s, br, 1H), 5.66 (d, J=8.0Hz, 1H), 4.94- 5.30 (m, 6H), 3.74-4.43 (m, 5H), 2.36 (s, 3H), 1.33-1.42 (m, 6H), 1.15-1.23 (m, 6H); 31 PNMR(CD 3 OD) δ 8.58; MS (m / z) 558 (M+H). ...

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PUM

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Abstract

The invention relates to a novel nucleoside phosphate / phosphonate prodrug containing non-naturalD-amino acid ester, a preparation method and a medical purpose thereof. The novel nucleoside phosphate / phosphonate prodrug containing a substituted benzyl group is a compound shown in a formula (I) or a formula (II) or its isomer or medicinal salt, which can be used as the prodrug of various nucleoside analogues such as acyclic nucleoside, carbocyclic nucleoside, and furan ring nucleoside, biological activity of the nucleoside compound can be enhanced, so that the derivative can be used for treating virus infection and cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a novel nucleoside phosphoramidate / phosphonate prodrug containing a non-natural configuration D-amino acid ester and a preparation method and application thereof. Background of the Invention [0002] Nucleoside compounds are deoxyribonucleic acid and ribonucleic acid, that is, the structural monomers of biological genetic DNA and RNA. Therefore, 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 disrupt the replication of viral genes by blocking the growth of viral nucleic acid chains and become antiviral drugs ( figure 1 ). [0003] like figure 1 As shown, nucleosides must first be activ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H19/207C07F9/6561C07F9/6512A61K31/7072A61K31/7076A61K31/675A61K31/7068A61P31/18A61P31/20A61P31/14A61P35/00
Inventor 刘沛
Owner SHENZHEN VYBIO PHARM TECH CO LTD
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