Phosphonate nucleotide compounds

• US 5,840,716 A
• Filed: 01/17/1997
• Issued: 11/24/1998
• Est. Priority Date: 01/18/1996
• Status: Expired due to Fees

• Current Assignee: Mitsubishi Chemical Corporation (Mitsubishi Chemical Group Corp.)
• Original Assignee: Mitsubishi Chemical Corporation (Mitsubishi Chemical Group Corp.)
• Inventors: Yuasa, Satoshi, Ueda, Naoko, Kamiya, Naohiro, Takashima, Hideaki, Sekiya, Kouichi, Ubasawa, Masaru
• Primary Examiner(s): Marschel, Ardin H.
• Assistant Examiner(s): Riley, Jezia
• Application Number:
  US08/785,606
• Time in Patent Office: 676 Days
• Field of Search: 514/75, 514/79, 514/80, 514/81, 544/243, 544/244
• US Class Current: 514/75
• CPC Class Codes: A61P 31/12 Antivirals
• 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 having antiviral activity and is useful for an orally available and highly safe antiviral agent, which is represented by the following formula (I): ##STR1## wherein R¹ represents hydrogen, a C₁ -C₆ alkoxy, a halogen-substituted C₁ -C₄ alkoxy, halogen, amino, or nitro; R² and R³ independently represent hydrogen, a C₁ -C₂₂ alkyl, an acyloxymethy, an acylthioethyl, or a halogen-substituted ethyl; R⁴ represents hydrogen, a C₁ -C₄ alkyl, a C₁ -C₄ hydroxyalkyl, or a halogen-substituted C₁ -C₄ alkyl; and X represents carbon or nitrogen.

Claims

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

##STR8## wherein R¹ represents hydrogen atom or a C₁ -C₆ alkoxy group, R² and R³ independently represent hydrogen atom, a C₁ -C₂ 2 alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms;

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

X represents a carbon atom or a nitrogen atom.

2. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein R¹ represents hydrogen atom or a C₁ -C₄ alkoxy group;

and R² and R³ independently represent hydrogen atom, a C₁ -C₂ 2 alkyl group, or an ethyl group substituted with one or more halogen atoms.

3. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein R¹ represents hydrogen atom or a C₁ -C₄ alkoxy group;

R² and R³ independently represent hydrogen atom, a C₁ -C₂ 2 alkyl group, or 2,2,2-trifluoroethyl group; and

R⁴ represents hydrogen atom or methyl group.

4. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein R¹ represents hydrogen atom or a C₁ -C₄ alkoxy group;

R² and R³ independently represent hydrogen atom or 2,2,2-trifluoroethyl group; and

R⁴ represents hydrogen atom or methyl group.

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

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- (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- phosphonylmethoxy!ethyl!-6-phenylthiopurine;

2-amino-9- 2- phosphonylmethoxy!ethyl!-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; and

2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-p-isobutoxyphenylthiopurine.

6. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein R¹ is hydrogen atom or a C₁ -C₄ alkoxy group;

R² and R³ represent 2,2,2-trifluoroethyl group; and

R⁴ represents hydrogen atom or methyl group.

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

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; and

2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-p-isobutoxyphenylthiopurine.

8. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein R¹ is hydrogen atom or a C₁ -C₄ alkoxy group;

R² and R³ represent 2,2,2-trifluoroethyl group; and

R⁴ represents hydrogen atom.

9. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 8, which is selected from the group consisting of:

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; and

2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-p-isobutoxyphenylthiopurine.

10. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein R¹ represents hydrogen atom or a C₁ -C₂ alkoxy group;

R² and R³ represent 2,2,2-trifluoroethyl group; and

R⁴ represents hydrogen atom.

11. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein the compound is 2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-phenylthiopurine.

12. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein the compound is 2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-p-methoxyphenylthiopurine.

13. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein the compound is 2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-m-methoxyphenylthiopurine.

14. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein the compound is 2-amino-9- 2- -(bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-o-methoxyphenylthiopurine.

15. The phosphonate nucleotide compound or its salt, or a hydrate or a solvate thereof according to claim 1, wherein the compound is 2-amino-9- 2- bis(2,2,2-trifluoroethyl)phosphonylmethoxy!ethyl!-6-p-ethoxyphenylthiopurine.

16. A pharmaceutical composition comprising a substance selected from the group of the phosphonate nucleotide compound and its salt, and a hydrate and a solvate thereof according to claim 1 together with a pharmaceutically acceptable additive.

17. A method for the treatment of a viral infection which comprises administering to a patient in need of such treatment an effective amount of a substance selected from the group of the phosphonate nucleotide compound and its salt, and a hydrate and a solvate thereof as defined in claim I.

18. A method according to claim 17 wherein the virus is hepatitis B virus.