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Phosphate nucleotide compound'

A technology of phosphonate and compounds, applied in the fields of compounds of group 5/15 elements of the periodic table, organic chemistry, chemical instruments and methods, etc., can solve AIDS and hepatitis B virus diseases without ideal treatment methods, without bone marrow cells Growth inhibition, patient difficulties, etc.

Inactive Publication Date: 2003-06-25
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Parenteral treatment is difficult for patients who are not hospitalized, which means that there is no ideal treatment for AIDS and hepatitis B virus diseases that require long-term treatment
[0004] On the other hand, the present inventors first discovered that specific ester derivatives of phosphonate nucleotides can show high oral absorbability (EP 632048 communiqué), and further found that by introducing a base moiety into a specific Antiviral drugs without toxicity such as bone marrow cell growth inhibition and mutagenicity can be obtained in the structure, but the current status is not practical

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] 2-Amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl)ester (Compound No.3) preparation of

[0083] 87g (670mmol) 2-chloroethyl chloromethyl ether and 200g (610mmol) three (2,2,2-trifluoroethyl) phosphite were reacted at 160°C for 7 hours to obtain quantitative 2-[bis( 2,2,2-Trifluoroethyl)phosphonomethoxy]ethyl chloride.

[0084] 206 g of 2-(phosphonomethoxy)ethyl chloride bis(2,2,2-trifluoroethyl) ester was dissolved in 2000 ml of methyl ethyl ketone and refluxed with 270 g of sodium iodide for 8 hours. After the reaction, the reaction mixture was cooled to room temperature, then concentrated to dryness. The residue was dissolved in chloroform / hexane, then adsorbed on a silica gel column, and eluted with chloroform / hexane to obtain quantitative 2-(phosphonomethoxy)ethyl iodide bis(2,2,2-tris Fluoroethyl) ester.

[0085] Suspend 15.0g (88mmol) of 2-amino-6-chloropurine in 360ml of dimethylformamide, and mix the resulting suspe...

Embodiment 2

[0089] 2-Amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine methyl (2,2,2-trifluoroethyl) ester (compound No. 9 ) preparation

[0090] 100mg of 2-amino-9-[2-[bis(2,2,2-trifluoroethoxy)phosphonomethoxy]ethyl]-6-(4-hydroxyphenylthio)purine (No. Compound) was dissolved in 0.35N ammonia-methanol solution, left at room temperature for 40 minutes, and then the solvent was distilled off to obtain the target compound.

[0091] 1 H-NMR (DMSO-d6, δ): 3.66 (d, J=4.5Hz, 3H), 3.83-3.87 (m, 2H), 4.00 (d, J=8.1Hz, 2H), 4.18-4.22 (m, 2H), 4.52-4.60(m, 2H), 6.23(s, 2H), 6.83(d, J=8.4Hz, 2H), 7.37(d, J=8.4Hz, 2H), 7.89(s, 1H), 9.81(s, 1H)

Embodiment 3

[0093] 2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester (compound No. 18) preparation

[0094] 60mg of 2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl)ester (No. compound) was dissolved in 1N ammonia solution, and after standing at room temperature for 3 hours, the solvent was distilled off to obtain the target compound.

[0095] 1 H-NMR (DMSO-d6, δ): 3.51-3.54 (m, 2H), 3.74-3.77 (m, 2H), 4.03-4.12 (m, 2H), 4.14-4.16 (m, 2H), 6.20 (s , 2H), 6.82(d, J=8.4Hz, 2H), 7.12(b, 3H), 7.36(d, J=8.4Hz, 2H), 8.00(s, 1H), 9.81(s, 1H)

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Abstract

2-Amino-6-arylthiopurine phosphonate shows no toxicity (inhibition of bone marrow cell growth, mutagenicity, etc.) but a high antiviral activity, has an oral absorbability and a high safety and can be produced in a short process. Thus, use of this compound makes it possible to provide an excellent antiviral agent which can be efficiently produced.

Description

technical field [0001] The present invention relates to a novel phosphonate nucleotide compound. More particularly, it relates to novel phosphonate nucleotide compounds and their salts, as well as their hydrates and solvates, which have antiviral activity and are useful as pharmaceuticals. Background technique [0002] Infectious viral diseases are being recognized as medically important problems, and for the purpose of treating such diseases, research is under way to develop drugs that have antiviral activity and, at the same time, have no inhibitory activity on the proliferation of normal cell lines. For example, phosphonate nucleotides are currently under extensive investigation as selective antiviral agents, in particular, 9-(2-phosphonomethoxy)ethyladenine (PMEA), 9- (2-phosphonomethoxy) ethyl-2,6-diaminopurine (PMDAP), etc., for herpes simplex type 1 and type 2 (HSV-1 and HSV-2), human immunodeficiency virus (HIV), Human hepatitis B virus (HBV) is very effective (Yok...

Claims

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Application Information

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IPC IPC(8): A61K31/675A61K31/685A61P31/20A61P31/22C07F9/6561
CPCA61K31/675C07F9/65616C07F9/6561A61K31/685A61P31/20A61P31/22
Inventor 姥泽贤关谷浩一
Owner MITSUBISHI TANABE PHARMA CORP
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