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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 hydrophilicity affects its development as a clinical drug

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0028] (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 for 6h. After spin-drying, a yellow oily substance is obtained. Add 100ml of a mixed solvent of dichloromethane and methanol at a ratio of 1:1 to fully dissolve and filter. The filtrate is spin-dried, and the residue After separation by silica gel column chromatography, 2.04 (71.5%) was obtained as a pale yellow solid. 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).

Embodiment 2

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

[0030] Dissolve an equal amount of (R)-9-[2-[(hexadecyloxypropyl)phosphomethoxy]propyl]adenine and fumaric acid in hot isopropanol and stir for 0.5h, then cool and analyze at room temperature. crystal, and the precipitated solid was filtered off 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).

Embodiment 3

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

[0032] An equal amount of (R)-9-[2-[(hexadecyloxypropyl)phosphomethoxy]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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