Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity

A tenofovir and virus replication technology, applied in the field of tenofovir monoester compound, can solve problems affecting development and poor bioavailability of tenofovir

Active Publication Date: 2006-08-02
CINKATE PHARMA INTERMEDIATES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the poor bioavailability of tenofovir with strong

Method used

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  • Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity
  • Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity
  • Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0027] Example 1: Preparation of (R)-9-[2-[(hexadecyloxypropyl)phosphate methoxy]propyl]adenine (5)

[0028] Add (R)-9-[2-(phosphomethoxy)propyl]adenine 1.44g (PMPA 5.0mmol), DMF20ml, 1-bromo-3-hexadecyloxypropane 1.82g (5.0mol), triethyl Mix 0.61g (6.0mmol) of amine, heat to 80°C and stir to react for 6h. After spin-drying, a yellow oil is obtained. Add 100ml of a 1:1 mixed solvent of dichloromethane and methanol to fully dissolve it and filter. After silica gel column chromatography separation, a pale yellow solid 2.04 (71.5%) was obtained. 1 HNMR(DMSO)δ, (ppm): 0.838(3H, t, CH 3 ), 0.919-0.933(3H, d, CH 3 ), 1.134-1.225 (26H, m, 13×CH 2 ), 1.414-1.475 (2H, m, CH 2 ), 1.606-1.638 (2H, m, CH 2 ), 3.128-3.416 (6H, m, 3×OCH 2 ), 3.642 (2H, s, OCH 2 P), 3.837-3.850 (1H, m, CH), 4.084-4.269 (2H, m, NCH 2 ), 7.109 (2H, s, NH 2 ), 8.098, 8.345 (2H, s, respectively H on the purine ring).

Example Embodiment

[0029] Example 2: Preparation of (R)-9-[2-[(hexadecyloxypropyl)phosphate methoxy]propyl]adenine fumarate (6)

[0030] Dissolve equal amounts of (R)-9-[2-[(hexadecyloxypropyl) methoxy phosphate] propyl] adenine and fumaric acid in hot isopropanol, stir for 0.5h, and cool down at room temperature for precipitation Crystal, the precipitated solid was filtered and washed with ether to obtain a white solid. 1 HNMR(DMSO)δ, (ppm): 0.833(3H, t, CH 3 ), 0.910-0.926(3H, d, CH 3 ), 1.136-1.219 (26H, m, 13×CH 2 ), 1.428-1.476 (2H, m, CH 2 ), 1.601-1.630 (2H, m, CH 2 ), 3.127-3.419 (6H, m, 3×OCH 2 ), 3.642 (2H, s, OCH 2 P), 3.835-3.853 (1H, m, CH), 4.096-4.267 (2H, m, NCH 2 ), 6.63 (2H, s, H on the double bond of fumaric acid), 6.998 (2H, s, NH 2 ), 8.103, 8.339 (2H, s, respectively H on the purine ring).

Example Embodiment

[0031] Example 3: Preparation of (R)-9-[2-[(hexadecyloxypropyl)phosphate methoxy]propyl]adenine sodium salt (7)

[0032] Equal amounts of (R)-9-[2-[(hexadecyloxypropyl) methoxy phosphate] propyl] adenine and NaOH were dissolved in water, stirred for 0.5 h, and freeze-dried to obtain a white flocculent solid.

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Abstract

The present invention relates to one group of Tenofovir monoester compounds and their alkali/acid composites, synthesis process and antiviral application. Extracorporeal experiment shows that the compounds of the present invention have HIV-1 virus copy and HBV virus copy inhibiting activity. The present invention lays foundation for the research and development of the compounds in antiviral application.

Description

Technical field: [0001] The invention relates to a group of tenofovir (PMPA) monoester compounds and complexes of the above monoester compounds and alkali / acid; the invention also relates to a synthesis method of the compound and an antiviral application. Background technique: [0002] Tenofovir is an acyclic nucleoside antiviral compound, which has a strong inhibitory effect on retroviruses and has no cross-resistance with other nucleoside drugs used in clinical practice. However, the poor bioavailability of tenofovir with strong hydrophilicity affects its development as a clinical drug. To increase their bioavailability, they are usually formulated as ester prodrugs. Tenofovir DF (WO99 / 05150), a fumaric acid complex of isopropoxymethyl ester of tenofovir, was approved by the FDA in 2001 as a drug for the treatment of HIV infection. The strongest, less nephrotoxic HIV reverse transcriptase inhibitor AIDS drug. The oral bioavailability of tenofovir DF has been significant...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/12
Inventor 李卓荣蔡步林彭宗根李玉环陶佩珍
Owner CINKATE PHARMA INTERMEDIATES
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