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Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs

A prodrug and pharmacy technology, applied in the field of double liver targeting phosphoramidate or aminophosphonate prodrug, can solve the problem of unreported biological activity, inability to effectively cleave active nucleoside phosphate, and unproven biological applicability And other issues

Active Publication Date: 2015-05-20
HENAN GENUINE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no biological activity was reported for any of the compounds
Therefore, R b Phosphoramidates that are unsubstituted alkyl or benzyl groups on the phenyl ring have never demonstrated biological utility, probably because these groups (alkyl or benzyl groups) in nucleoside phosphoramidate prodrugs ) are too stable to be cleaved efficiently to produce active nucleoside phosphates

Method used

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  • Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs
  • Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs
  • Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0248] Example 1. Preparation of monochlorophosphoramidate 3.

[0249]

[0250] To a solution of phosphorus oxychloride (3.07 g, 20 mmol) in THF (40 mL) was added 2-methylbenzyl alcohol (1, 2.44 g, 20 mmol) and triethylamine (2.02 g, 20 mmol) at -78°C. THF (10 mL), and the mixture was stirred at -78°C for 3 hours. At -78°C, L-alanyl isopropyl ester hydrochloride (3.35 g, 20 mmol) and THF (10 mL) containing triethylamine (4.04 g, 40 mmol) were successively added to the resulting mixture, and at -78 The mixture was stirred at °C for 1 hour, then at room temperature overnight to obtain a crude compound 3 reaction mixture.

example 2

[0251] Example 2. Similarly, benzyl monochlorophosphoramidate 3' was prepared.

[0252]

example 3

[0253] Example 3. Preparation of Chiral Reagent 4 as a Diastereomerically Enriched Isomer.

[0254]

[0255] As in Example 1, a mixture of compound 3 was prepared on a 20 mmol scale. A solution of pentafluorophenol (20 mmol) and triethylamine (20 mmol) was added to the mixture. To the mixture was added another portion of triethylamine (20 mmol) and the mixture was stirred at room temperature for 4 hours. EtOAc (200 mL) was added and the mixture was washed with water and brine, and washed with Na 2 SO 4 dry. The solvent was removed and the residue was purified by silica gel column chromatography (5-50% EtOAc in hexanes) to give the crude compound as a mixture of diastereoisomers. 1 H-NMR (CDCl 3 ):δ7.18-7.36(m,4H),5.23(dd,J=7.2Hz,1H),5.02(m,1H),4.00(m,1H),3.76(m,1H),2.38,2.37( ss, 3H), 1.42, 1.37 (d, J=7.2Hz, 2H), 1.24 (m, 9H). Recrystallization of the mixture of diastereomers from EtOAc-hexane afforded diastereomerically enriched reagent 4. 1 H-NMR (CDCl 3):δ7.17-7...

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Abstract

This application discloses phosphoramidate and phosphonoamidate prodrugs of alcohol-based therapeutic agents, such as nucleosides, nucleotides, acyclonucleosides, C- nucleosides, and C-nucleotides, and use of these prodrugs for treatment of diseases or disorders, including infectious diseases and cancers. This application also discloses a general method for enhancing bioavailability and / or liver-targeting property of alcohol drugs through converting the alcohol drugs to phosphoramidate or phosphonoamidate prodrugs, and methods of preparation of these prodrugs.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61 / 689,936, filed June 16, 2012, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to double liver targeting phosphoramidate or aminophosphonate prodrug, and its therapeutic use and preparation method. Background technique [0004] Nucleoside analogs have been developed as antiviral and anticancer agents. Nucleotide kinases phosphorylate nucleosides to their corresponding 5'-monophosphates, which are further converted to their diphosphates and triphosphates by cellular nucleotide kinases. [0005] Some nucleosides are less active because they are not efficiently phosphorylated by kinases or are not substrates for kinases at all, as evidenced by the observation that some inactive nucleosides become Possess potent activity against certain viruses in vitro. Nucleo...

Claims

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Application Information

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IPC IPC(8): A01N43/08A61K31/70A61P31/12
CPCA61P31/12C07H19/10C07H19/207
Inventor 常俊标刘润聪黄强王振
Owner HENAN GENUINE BIOTECH CO LTD
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