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New condensed tricyclonucleoside compound containing acyclovir fragment and its preparation method

A nucleoside compound, compound technology, applied in the direction of organic chemistry, antiviral agent, etc., can solve the problems of low bioavailability, poor water solubility, etc., and achieve the effect of high biological activity

Inactive Publication Date: 2003-09-24
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the relatively poor water solubility and low bioavailability of such drugs, there is still a need to find new antiviral drugs

Method used

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  • New condensed tricyclonucleoside compound containing acyclovir fragment and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]9-(2-hydroxyethoxy)methyl-2-amino-6-N'-substituted benzylidene hydrazino-6-deoxy-9H-purine synthetic general method, with 9-(2-hydroxyethyl Oxy)methyl-2-amino-6-N'-benzylidenehydrazino-6-deoxy-9H-purine as an example: Reaction step 1

[0048] 9-(2-Hydroxyethoxy)methyl-2-amino-6-hydrazino-6-deoxy-9H-purine

[0049] Take vacuum-dried 9-(2-hydroxyethoxy)methyl-2-amino-6-chloro-6-deoxy-9H-purine (3.0g, 0.0105mol) and add it to 10ml of absolute ethanol, stir After dissolving, hydrazine hydrate (1.0 g, 0.020 mol) was added, and 2.45 g of white solid was precipitated after reacting for 1 hour, with a yield of 98%. m.p.: 179-180°C. EI-MS m / z 239 (M + ) 1 H-NMR (400MHz, DMSO-d 6 )δ3.47(t, 4H, OCH 2 CH 2 O), 4.41 (S, 2H, NHNH 2 , disappear after adding D2O), 4.63 (s, H, OH, disappear after adding D2O), 5.37 (s, 2H, NCH 2 O), 5.94(s, 2H, CNH 2 , disappeared after adding D2O), 7.81 (s, H, 8-H) elemental analysis (C 8 h 13 N 2 o 2 ):

[0050] C% H% N% Calculate...

Embodiment 2

[0054] The synthetic general method of the tricyclic nucleoside compound containing nine-membered heterocycle, with 3-amino-14-(2-hydroxyl-ethoxymethyl)-8-(4-methoxyl-phenyl) 2,4 , 6, 7, 9, 10, 12, 14-octaaza-tricyclo [9.2.2.0 5，13 ]Tetradecane-1,3,5(13),7,11-pentaene-9,10-dicarboxylate diethyl ester as an example:

[0055] Take vacuum-dried 9-(2-hydroxyethoxy)methyl-2-amino-6-N'-(4-methoxybenzylidene)-hydrazino-6-deoxy-9H-purine (0.15 g, 0.42mmol), put into a 25ml eggplant-shaped flask, add 8ml of diethyl azodicarboxylate (DEAD) and 2ml of methanol, heat to 120°C, and react for 1 hour, the solution is clear, and thin-layer chromatography checks (silica gel prefabricated plate, developer dichloromethane:methanol=10:1) shows that reaction is complete, and the R of product f = 0.78. Silica gel column chromatography with ethyl acetate as the eluent gave 0.132 g of a light yellow solid with a yield of 61%. m.p.: 214-215°C. EI-MS m / z 529 (M + ) 1 H-NMR (400MHz, DMSO-d 6 )δ1...

Embodiment 3

[0058] 3-Amino-14-(2-hydroxy-ethoxymethyl)-8-(phenyl)-2,4,6,7,9,10,12,14-octaaza-tricyclo[9.2.2.0 5.13 ] Tetradecane-1,3,5(13), 7,11-pentaene-9,10-dicarboxylate diethyl ester (C-1)

[0059] Take vacuum-dried 9-(2-hydroxyethoxy)methyl-2-amino-6-N'-benzylidene-hydrazine-6-deoxy-9H-purine (0.15g, 0.495mmol), put Put into a 25ml eggplant-shaped flask, add DEAD8ml and anhydrous methanol 2ml, heat to 120°C, react for 1 hour and then the solution is clear, TLC inspection (silica gel prefabricated plate, developer dichloromethane:methanol=10:1) Shows complete disappearance of reactants. Column chromatography, the eluent was ethyl acetate, and 0.105 g of light yellow solid was obtained with a yield of 46%. m.p.: 122-123°C. EI-MS m / z 499 (M + ) 1 H-NMR (400Hz, DMSO-d 6 )δ1.185(t, 3H, OCH 2 CH 3 ), 1.22(t, 3H, OCH 2 CH 3 ), 3.49(t, 2H, OCH 2 CH 2 O), 3.57(t, 2H, OCH 2 CH 2 O), 4.15(q, 2H, OCH 2 CH 3 ), 4.20 (q, 2H, OCH 2 CH 3 ), 4.585 (s, H, OH, adding D 2 Disappear af...

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Abstract

The present invention discloses a new condensed tricyclonucleoside compound containing acyclovir fragment and its preparation method. Said invented compound has ontiviral activity, specially has the activity for resisting DNA virus. It also has the latent antitumor activity and high biological activity.

Description

technical field [0001] The invention relates to an antiviral drug, in particular to a new fused tricyclic nucleoside compound containing acyclovir fragments and a preparation method thereof. Background technique [0002] Viral diseases are common diseases that seriously threaten human health and life, especially the harm of AIDS virus (AIDS) and infectious viruses. In the past two decades, acyclic nucleoside antiviral drugs represented by acyclovir (Acyclovir I) and ganciclovir (Ganciclovir II) have been widely used clinically. However, due to the relatively poor water solubility and low bioavailability of such drugs, there is still a need to find new antiviral drugs. [0003] In order to improve bioavailability and water solubility, many studies have been carried out in the fields of medicine and chemistry, Huryn D.M et al. in related development review (ADIS-Driven Nucleoside Chemistry, Chem.Rev 1992, 1271-1295), Li Fangyu, Ma Weiyong et al. in US60 Disclosed in / 295,086...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P31/20C07D473/00C07D487/18
Inventor 马维勇王芳肖旭华赵建宏
Owner SHANGHAI INST OF PHARMA IND
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