Phosphonate nucleotide compound

• US 6,767,900 B2
• Filed: 11/04/2002
• Issued: 07/27/2004
• Est. Priority Date: 02/29/2000
• Status: Expired due to Fees

• Current Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Original Assignee: Mitsubishi Tanabe Pharma Corporation (Mitsubishi Chemical Group Corp.)
• Inventors: Sekiya, Kouichi, Ubasawa, Masaru
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US10/220,126
• Publication Number:
  US 20030153534A1
• Time in Patent Office: 631 Days
• Field of Search: 544/244, 514/81
• US Class Current: 514/81
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

A phosphonate nucleotide compound represented by the following formula (I) or a salt thereof, or a hydrate or solvate thereof:

wherein,

R¹ is a hydroxyl group; each of R² and R³ is independently a hydrogen atom, a C₁-C₂₂ alkyl group, an alkanoyloxymethyl group, an alkanoylthioethyl group, or an ethyl group substituted by one or more halogen atoms; R⁴ is a hydrogen atom, a C₁-C₄ alkyl group, a C₁-C₄ hydroxyalkyl group, or a C₁-C₄ alkyl group substituted by one or more halogen atoms; and X is CH or a nitrogen atom.

Claims

1. A phosphonate nucleotide compound represented by the following formula (I) or a salt thereof, or a hydrate or solvate thereof:

wherein,

R¹ is a hydroxyl group;

each of R² and R³ is independently a hydrogen atom, a C₁-C₂₂ alkyl group, an alkanoyloxymethyl group, an alkanoylthioethyl group, or an ethyl group substituted by one or more halogen atoms;

R⁴ is a hydrogen atom, a C₁-C₄ alkyl group, a C₁-C₄ hydroxyalkyl group, or a C₁-C₄ alkyl group substituted by one or more halogen atoms; and

X is CH or a nitrogen atom.

2. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 1, wherein each of R² and R³ is independently a hydrogen atom, a C₁-C₂₂ alkyl group, or an ethyl group substituted by one or more halogen atoms.

3. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 1, wherein each of R² and R³ is independently a hydrogen atom, a C₁-C₂₂ alkyl group, or a 2,2,2-trifluoroethyl group;

and R⁴ is a hydrogen atom or a methyl group.

4. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 3, which is selected from the group consisting of the following compounds:

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine bis (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine bis (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine bis (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(4-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(3-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(2-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine methyl(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine methyl(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine methyl(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine methyl(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine methyl(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine methyl(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(4-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(3-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(2-hydroxyphenylthio)purine (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(4-hydroxyphenylthio)purine;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(3-hydroxyphenylthio)purine; and

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(2-hydroxyphenylthio)purine.

5. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 1, wherein each of R² and R³ is a 2,2,2-trifluoroethyl group;

and R⁴ is a hydrogen atom or a methyl group.

6. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 5, which is selected from the group consisting of the following compounds:

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine bis (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine bis (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine bis (2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(4-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(3-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester;

2-amino-9-[2-(phosphonomethoxy)propyl]-6-(2-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester.

7. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 1, wherein each of R² and R³ is a 2,2,2-trifluoroethyl group;

and R⁴ is a hydrogen atom.

8. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 7, which is 2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(2-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester.

9. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 7, which is 2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(3-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester.

10. The phosphonate nucleotide compound or salt thereof, or hydrate or solvate thereof according to claim 7, which is 2-amino-9-[2-(phosphonomethoxy)ethyl]-6-(4-hydroxyphenylthio)purine bis(2,2,2-trifluoroethyl) ester.

11. A pharmaceutical composition, which comprises a substance selected from the group consisting of the compound and salt thereof, and hydrate and a solvate thereof according to claim 1, and a pharmacologically acceptable pharmaceutical additive.

12. A method for treating a viral infection caused by a virus selected from the group consisting of herpes simplex virus type I, herpes simplex virus type 2 cytomegalovirus, varicella-zoster virus, and hepatitis B virus, which comprises administering a therapeutically effective amount of the compound according to claim 1 to a patient in need thereof.

13. The method according to claim 12, wherein the virus is a hepatitis B virus.