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Structure and Synthesis of Novel Benzyl Phosphoramidate Prodrugs of Nucleoside Compounds

A benzyl phosphoramidate and benzyl phosphoramidate functional technology, applied in the field of valence, can solve the problems of carcinogenic toxicity and lower bioavailability

Active Publication Date: 2015-08-05
刘沛
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the phenols produced by the metabolism of McGuigan prodrugs have potential carcinogenic toxicity, and their lipid groups are easily hydrolyzed by esterases widely distributed in the intestinal tract, which reduces their bioavailability

Method used

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  • Structure and Synthesis of Novel Benzyl Phosphoramidate Prodrugs of Nucleoside Compounds
  • Structure and Synthesis of Novel Benzyl Phosphoramidate Prodrugs of Nucleoside Compounds
  • Structure and Synthesis of Novel Benzyl Phosphoramidate Prodrugs of Nucleoside Compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] A solution of 30 mmoles of appropriately substituted benzyl alcohol and triethylamine (4.25 mL, 30.5 mmol) in dry benzene (125 mL) was slowly added dropwise to freshly distilled phosphorus oxychloride (10 mL, 107 mmol) at 0-10 °C In dry benzene (50 mL), the reaction solution was slowly warmed up and stirred at room temperature overnight. The reaction mixture was filtered under dry conditions, and the filtrate was concentrated to give substituted benzyl phosphoryl dichloride (12).

Embodiment 2

[0050]

[0051] Dissolve substituted benzylphosphoryl dichloride (12) (4mmol) and appropriately substituted benzylamine (13, 4mmol) into dry dichloromethane (50mL), slowly add three Ethylamine (0.6 mL, 4.3 mmol) in dichloromethane (10 mL). The reaction solution was stirred and reacted at room temperature for 5 hours, the solvent was evaporated, dry diethyl ether (25 mL) was added to the residue, filtered under nitrogen protection, and the N, O-disubstituted benzylphosphoryl chloride (14) obtained after the filtrate was concentrated could be directly For the next reaction without purification.

[0052] The obtained N,O-disubstituted benzyl phosphoryl chloride (14) can also be dissolved in dry tetrahydrofuran (4 mL) to prepare a 1 mol / L solution for use.

Embodiment 3

[0054]

[0055] At room temperature, N-methylimidazole (410 mg, 5 mmol) was slowly added dropwise to a suspension of uracil (244 mg, 1 mmol) in anhydrous THF (5 mL), and stirred at room temperature for 30 minutes. Then, a solution of N, O-dibenzylphosphoryl chloride (14b, 618 mg, 2 mmol) in THF (2 mL) was slowly added to the above reaction mixture, and the reaction was stirred overnight at room temperature. The reaction solution was concentrated by rotary evaporation, the residue was dissolved in chloroform (10 mL), the organic phase was washed with dilute hydrochloric acid (1M, 10 mL), saturated sodium bicarbonate (10 mL), water (15 mL), and dried (Na 2 SO 4 ), concentrated, and the synthesized uracil benzyl phosphoramidate was purified by silica gel column chromatography (dichloromethane:methanol=10:1). MS(m / e)518(M+H). 1 H NMR (CD 3 OD, 400MHz) δ7.66(d, J=6.8Hz, 0.5H), 7.58(d, J=8.4Hz, 0.5H), 6.98-7.32(m, 9H), 5.72(d, J=5.6Hz, 0.5H), 5.70(d, J=5.2Hz, 0.5H), 5.47(, d,...

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Abstract

The invention discloses a novel benzyl amido phosphate structure shown as a formula (I). The novel benzyl amido phosphate ester structure can be taken as a prodrug of various nucleoside compounds (including acyclic nucleoside, carbocycle nucleoside, furan ring nucleoside and the like) for enhancing the bioactivity of the nucleoside compounds, so that the novel benzyl amido phosphate ester structure is applied to treatment of virus infection and cancers.

Description

technical field [0001] The present invention relates to a novel benzyl phosphoramidate prodrug (1) of a class of nucleoside compounds, as an equivalent of nucleoside monophosphate, its structural characteristics and its preparation method. [0002] Background of the invention [0003] Nucleoside compounds are 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. [0004] Since the 1960s, many biologically active nucleoside compounds have been used to treat various viral infections such as herpes, AIDS, hepatitis B and C. A large number of studies have confirmed that the mechanism by which nucleosides produce biological activity is the same. To work, nucleoside drugs must be activated into their corresponding nucleoside triphosphates before they can exhibit medicinal activity. Specifically, nucleosides are ofte...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61K47/48A61K31/7076A61P31/12A61P35/00A61K47/54
Inventor 刘沛
Owner 刘沛
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