Novel acyclic nucleoside phosphonic acid and its ester derivatives and pharmaceutical use thereof

A technology of nucleoside phosphonic acid and derivatives, which is applied in the field of new acyclic nucleoside phosphonic acid and its ester derivatives and its medical uses, can solve the problems that do not involve purine phosphonic acid and its ester derivatives and the like

Active Publication Date: 2006-09-06
广东京豪生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] None of the patents CN1040761C or CN1088712C relate to phenylthio-substituted purine phosphonic acid and its ester derivatives containing methylthio or methylamino substituents on the benzene ring

Method used

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  • Novel acyclic nucleoside phosphonic acid and its ester derivatives and pharmaceutical use thereof
  • Novel acyclic nucleoside phosphonic acid and its ester derivatives and pharmaceutical use thereof
  • Novel acyclic nucleoside phosphonic acid and its ester derivatives and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 2-amino-6-(2-methylthio-phenylthio)-9-[2-(phosphonomethoxy)ethyl]-purine (I 1 ) preparation

[0054] 1.1 Preparation of 2-(diisopropyl-phosphonomethoxy)-ethyl chloride

[0055] In a 1500ml three-necked flask, add 846g (705ml, 10.5mol) of 2-chloroethanol and 316g (10.9mol) of pulverized paraformaldehyde, and pass in dry hydrogen chloride gas under stirring for 24 hours. After the stirring was stopped, the reaction solution was divided into two layers; the lower layer was separated and dried with calcium chloride. After filtration, the filtrate was fractionated under reduced pressure, and the fraction with a boiling range of 80-84°C / 28-30mmHg was collected to obtain 743g of chloroethyl chloromethyl ether.

[0056] In a 3L reaction flask, add 180g (3mol) of isopropanol, 237g (3mol) of pyridine and 1000ml of petroleum ether, and cool in an ice bath. A solution of 137.5g (1mol) phosphorus trichloride in 400ml petroleum ether was added dropwise under vigorous sti...

Embodiment 2

[0066] Example 2 2-amino-6-(3-methylthio-phenylthio)-9-[2-(phosphonomethoxy)ethyl]-purine (I 2 ) preparation

[0067] According to the method of Example 1.4, 3-bromoanisole sulfide was used instead of 2-bromoanisole sulfide to prepare 3-methylthio-benzenethiol, with a boiling point of 72-78° C. / 1.5 mmHg.

[0068] According to the method of Example 1.5, replace 2-methylthio-benzenethiol and 2-amino-6-chloro-9-[2-(phosphonomethoxy)ethyl with 3-methylthio-benzenethiol ]-purine reaction to obtain I 2 , MP180°C (decomposition). Proton NMR spectrum: δ (ppm, DMSO): 8.11 (s, 1H); 7.60 (dd, 1H); 7.34-7.38 (m, 2H); 7.01-7.03 (m, 1H); 4.25 (b, 2H) ; 4.19 (t, 2H); 3.81 (t, 2H); 3.61 (d, 2H); 2.54 (s, 3H).

Embodiment 3

[0069] Example 3 2-amino-6-(4-methylthio-phenylthio)-9-[2-(phosphonomethoxy)ethyl]-purine (I 3 ) preparation

[0070] According to the method of Example 1.4, 4-bromoanisole sulfide was used instead of 2-bromoanisole sulfide to prepare 4-methylthio-benzenethiol, with a boiling point of 75-78° C. / 0.3 mmHg.

[0071] According to the method of Example 1.5, replace 2-methylthio-benzenethiol and 2-amino-6-chloro-9-[2-(phosphonomethoxy)ethyl with 4-methylthio-benzenethiol ]-purine reaction to obtain I 3 , MP185°C (decomposition). Proton NMR spectrum: δ(ppm, DMSO): 7.98(s, 1H); 7.50-7.53(d, 2H); 7.02-7.07(d, 2H); 4.22(b, 2H); 4.16(t, 2H) ; 3.82(t, 2H); 3.55(d, 2H); 2.52(s, 3H).

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Abstract

Disclosed is a non-cyclic nucleotide phosphonic acid represented by formula (I) and its ester derivative, its non-toxic pharmaceutically acceptable salts, or their hydrates or solvates, wherein R1 represents C1-C6 alkyl, X represents NH or S, R2 represents hydrogen, C1-C3 alkyl or halogen substituted alkoxy, C1-C3 alkyl or halogen substituted alkyl, halogen, R3 represents H, C1-C3 alkyl, C1-C3 hydroxyl substituted alkyl or C1-C3 alkyl substituted by more than one halogen atoms, R4 and R5 represent H, C1-C22 alkyl, phenyl, acylorxy or alkyl substituted by more than one halogen atoms. Z represents C or N.

Description

technical field [0001] The present invention relates to novel acyclic nucleoside phosphonic acid derivatives and their esters, their non-toxic pharmaceutically acceptable salts, or their hydrates or solvates, and pharmaceutical compositions containing these compounds as active ingredients, And the use of the pharmaceutical composition containing them as active ingredients as an antiviral drug, especially an anti-hepatitis B virus drug. Background technique [0002] The present invention relates to novel acyclic nucleoside phosphonic acid derivatives and their esters, their non-toxic pharmaceutically acceptable salts, or their hydrates or solvates, and pharmaceutical compositions containing these compounds as active ingredients, And the use of the pharmaceutical composition containing them as active ingredients as an antiviral drug, especially an anti-hepatitis B virus drug. [0003] Hepatitis B virus is one of the diseases with the highest incidence rate, and there are as m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/14A61P1/16
Inventor 靳永增仲荣德靳雪峰
Owner 广东京豪生物制药有限公司
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