Antiviral agent for drug-resistant virus

US 20030109498A1
Filed: 10/29/2001
Published: 06/12/2003
Est. Priority Date: 06/20/2001
Status: Abandoned Application

First Claim

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1. A method for treating a drug resistant virus disease, which comprises administering a pharmacologically effective amount of a phosphonate nucleotide compound represented by the following formula (I):

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Abstract

2-amino-6-arylthiopurinephosphonate used in the antiviral agent of the present invention has no toxicity such as bone marrow cell growth inhibition or mutagenicity, and has a high antiviral activity, oral absorbency and safety. Furthermore, the compound of the present invention is effective for a mutant virus which is known to exhibit resistance to the conventional antiviral agents. Therefore, the present invention can provide a useful antiviral agent which leads to the establishment of a method for treating hepatitis B, which is a medically important object.

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13 Claims

1. A method for treating a drug resistant virus disease, which comprises administering a pharmacologically effective amount of a phosphonate nucleotide compound represented by the following formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
- - 2. The method according to claim 1, wherein R¹is a hydrogen atom, a C₁-C₆alkoxy group, a C₁-C₄alkoxy group substituted by one or more halogen atoms, a halogen atom, an amino group, a hydroxyl group or a nitro group;
    - and each of R²and R³is independently a hydrogen atom, a C₁-C₂₂alkyl group or an ethyl group substituted by one or more halogen atoms.
  - 3. The method according to claim 1, wherein R¹is a hydrogen atom, a C₁-C₆alkoxy group, a C₁-C₄alkoxy group substituted by one or more halogen atoms, a halogen atom, an amino group, a hydroxyl group or a nitro group;
    - each of R²and R³is independently a hydrogen atom, a C₁-C₂₂alkyl group or a 2,2,2-trifluoroethyl group; and
      
      R⁴is a hydrogen atom or a methyl group.
  - 4. The method according to claim 1, wherein R¹is a hydrogen atom, a C₁-C₆alkoxy group, a C₁-C₄alkoxy group substituted by one or more halogen atoms, a halogen atom, an amino group, a hydroxyl group or a nitro group;
    - each of R²and R³is inpendently a hydrogen atom or a 2,2,2-trifluoroethyl group; and
      
      R⁴is a hydrogen atom or a methyl group.
  - 5. The method according to claim 4, wherein the phosphonate nucleotide compound is selected from the group consisting of the following compounds:
    - 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-methoxyphenylth iopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-methoxyphenylt hiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-methoxyphenylth iopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-ethoxyphenylthio purine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-phenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-phenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)ethyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-m-hydroxyphenylthiopurine; and
      
      2-amino-9-[2-(phosphonomethoxy)propyl]-6-o-hydroxyphenylthiopurine.
  - 6. The method according to claim 1, wherein each of R²and R³is a 2,2,2-trifluoroethyl group;
    - and R⁴is a hydrogen atom or a methyl group.
  - 7. The method according to claim 6, wherein the phosphonate nucleotide compound is selected from the group consisting of the following compounds:
    - 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-isopropoxyphenylthiopurine; and
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-o-isobutoxyphenylthiopurine.
  - 8. The method according to claim 1, wherein each of R²and R³is a 2,2,2-trifluoroethyl group;
    - and R⁴is a hydrogen atom.
  - 9. The method according to claim 8, wherein the phosphonate nucleotide compound is selected from the group consisting of the following compounds:
    - 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-ethoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isopropoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-isobutoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-butoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-propoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isopropoxyphenylthiopurine; and
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-isobutoxyphenylthiopurine.
  - 10. The method according to claim 1, wherein R¹is a hydrogen atom, a hydroxyl group or a C₁-C₂alkoxy group;
    - each of R²and R³is a 2,2,2-trifluoroethyl group; and
      
      R⁴is a hydrogen atom.
  - 11. The method according to claim 10, wherein the phosphonate nucleotide compound is selected from the group consisting of the following compounds:
    - 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-phenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-methoxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-m-hydroxyphenylthiopurine;
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-o-hydroxyphenylthiopurine; and
      
      2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-p-ethoxyphenylthiopurine.
  - 12. The method according to claim 1, wherein the drug resistant virus is a human immunodeficiency virus or hepatitis B virus.
  - 13. The method according to claim 1, wherein the drug resistant virus is a hepatitis B virus.

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Current Assignee
Mitsubishi Pharma Corporation (Mitsubishi Chemical Group Corp.)
Original Assignee
Mitsubishi Pharma Corporation (Mitsubishi Chemical Group Corp.)
Inventors
Yuasa, Satoshi, Kamiya, Naohiro, Omata, Masao

Application Number

US09/984,214
Publication Number

US 20030109498A1
Time in Patent Office

Days
Field of Search
US Class Current

514/81
CPC Class Codes

A61K 31/675 having nitrogen as a ring h...

A61P 31/12 Antivirals

Antiviral agent for drug-resistant virus

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Abstract

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13 Claims

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Antiviral agent for drug-resistant virus

First Claim

1 Assignment

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Subscription Required

0 Petitions

Subscription Required

Accused Products

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Abstract

Citations

13 Claims

Specification

Subscription Required

Solutions

Use Cases

Quick Links