Inhibiting Coronaviridae viral replication and treating Coronaviridae viral infection with nucleoside compounds

• US 20040259934A1
• Filed: 04/27/2004
• Published: 12/23/2004
• Est. Priority Date: 05/01/2003
• Status: Abandoned Application

• Current Assignee: David B. Olsen, Joanne E. Tomassini, Shi-Shan Mao, Steven S. Carroll
• Original Assignee: David B. Olsen, Joanne E. Tomassini, Shi-Shan Mao, Steven S. Carroll
• Inventors: Tomassini, Joanne E., Olsen, David B., Mao, Shi-Shan, Carroll, Steven S.
• Application Number:
  US10/832,945
• Publication Number:
  US 20040259934A1
• Time in Patent Office: Days
• US Class Current: 514/447
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/381 having five-membered rings

Abstract

Infection by a Coronaviridae virus (e.g., a coronavirus) and/or illness due to a Coronaviridae virus are treated or protected against by administration of a therapeutically or prophylactically effective amount of certain nucleoside compounds and derivatives thereof, either alone or in a composition comprising the nucleoside compound or its derivative and a pharmaceutically acceptable carrier. In addition, replication of a Coronaviridae virus is inhibited by administration of the nucleoside compounds and derivatives thereof, either alone or in pharmaceutical compositions. The nucleosides are particularly suitable for use in treating or prophylaxis of an infection by the SARS virus and/or in treating or prophylaxis of SARS, and for use in inhibiting replication of the SARS virus. The nucleoside compounds and derivatives can optionally be administered in combination with other agents active against the Coronaviridae virus and/or an illness due to the virus. The nucleoside compounds are also for use in the manufacture of medicaments for the inhibition of Coronaviridae virus replication, for the treatment or prophylaxis of Coronaviridae virus infection, and/or for the treatment or prophylaxis of an illness due to a Coronaviridae virus (e.g., the SARS virus). In addition, the compounds are for use as medicaments for the inhibition of Coronaviridae virus replication, for the treatment or prophylaxis of Coronaviridae virus infection, and/or for the treatment or prophylaxis of an illness due to a Coronaviridae virus.

Claims

1. A method for inhibiting replication of a Coronaviridae virus, for treating or prophylaxis of an infection by a Coronaviridae virus, or for treating or prophylaxis of an illness due to a Coronaviridae virus in a subject in need thereof, which comprises administering to the subject an inhibition effective amount or a therapeutically or prophylactically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

2. The method according to claim 1, wherein

Z is O;

R¹ is H, OH, C_1-3 alkyl-O—

, C_1-3 alkyl, C_1-3 haloalkyl, or C_1-3 alkyl mono-substituted with OH, amino, C_1-4 alkyl-O—

or C_1-4 alkyl-S—

;

R² is H, OH, amino, fluoro, C_1-4 alkyl-CH(NH₂)-carbonyloxy, C_1-16 alkylcarbonyloxy, mercapto, C_1-3 alkyl-O—

, C_1-3 alkyl, or C_1-3 haloalkyl;

R³ is H, OH, halogen, C_1-4 alkyl-CH(NH₂)-carbonyloxy, C_1-16 alkylcarbonyloxy, amino, C_1-3 alkyl-O—

, C_1-3 alkyl, or C_1-3 haloalkyl;

R⁴ is H, OH, halogen, C_1-16 alkylcarbonyloxy, amino, C_1-3 alkyl-O—

, C_1-3 alkyl, or C_1-3 haloalkyl;

R⁵ is H, C_1-4 alkyl-CH(NH₂)-carbonyl, C_1-16 alkylcarbonyl, P₃O₉H₄, P₂O₆H₃, or PO₃H₂; and

R⁶ and R⁷ are both H.

3. The method according to claim 2, wherein

R¹ is H, OH, methyl, methoxy, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R² is H, OH, fluoro, (CH₃)₂CHCH(NH₂)-carbonyloxy, C_1-16 alkylcarbonyloxy, or methoxy;

R³ is H, OH, fluoro, (CH₃)₂CHCH(NH₂)-carbonyloxy, C_1-16 alkylcarbonyloxy, amino, or methoxy;

R⁴ is H; and

R⁵ is H, (CH₃)₂CHCH(NH₂)-carbonyl, C_1-16 alkylcarbonyl, or P₃O₉H₄.

4. The method according to claim 3, wherein

R¹ is methyl;

and

R² and R³ are both OH.

5. The method according to claim 1, wherein

Q is:

A is N or C-R^w;

R⁸ is H, C_1-3 alkyl, halogen, azido, amino, C_1-4 alkylamino, or C_1-3 alkyl-O—

;

R⁹ and R¹⁰ are each independently H, OH, halogen, amino, C_1-4 alkylamino, di(C_1-4 alkyl)amino, or C_3-6 cycloalkylamino; and

R_w is hydrogen, cyano, methyl, halogen, or C(═

O)NH₂.

6. The method according to claim 5, wherein the compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof:

7. The method according to claim 6, wherein

R¹ is H, OH, methyl, methoxy, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R² is H, OH, fluoro, C_1-16 alkylcarbonyloxy, or methoxy;

R³ is H, OH, fluoro, (CH₃)₂CHCH(NH₂)-carbonyloxy, C-_1-16 alkylcarbonyloxy, amino, or methoxy; and

R⁵ is H, (CH₃)₂CHCH(NH₂)-carbonyl, C_1-16 alkylcarbonyl, or P₃O₉H₄.

8. The method according to claim 7, wherein

R¹ is methyl;

R² and R³ are both OH; and

R⁵ is H, (CH₃)₂CHCH(NH₂)-carbonyl, C_1-16 alkylcarbonyl, or P₃O₉H₄.

9. The method according to claim 8, wherein the compound is selected from the group consisting of:

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;

2′

-C-methyladenosine;

corresponding 5′

-triphosphates thereof;

and pharmaceutically acceptable salts thereof.

10. The method according to claim 9, wherein the compound is 4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, or a pharmaceutically acceptable salt thereof.

11. The method according to claim 1, wherein

Q is

W is O;

R¹¹ is H, C_1-3 alkyl, C_1-3 alkylamino, or halogen; and

R¹² is H, OH, halogen, amino, C_1-4 alkylamino, di(C_1-4 alkyl)amino, or C_3-6 cycloalkylamino.

12. The method according to claim 11, wherein

Z is 0;

R¹ is H, OH, methyl, methoxy, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R² is H, OH, fluoro, C_1-16 alkylcarbonyloxy, or methoxy;

R³ is H, OH, fluoro, (CH₃)₂CHCH(NH₂)-carbonyloxy, C_1-16 alkylcarbonyloxy, amino, or methoxy;

R⁴ is H;

R⁵ is H, (CH₃)₂CHCH(NH₂)-carbonyl, C_1-16 alkylcarbonyl, or P₃O₉H₄; and

R⁶ and R⁷ are both H.

13. The method according to claim 12, wherein

R¹ is methyl;

and

R² and R³ are both OH.

14. The method according to claim 13, wherein the compound is 2′

-C-methylcytidine, or a pharmaeutically acceptable salt thereof.

15. The method according to claim 1, which is a method for inhibiting replication of a Coronaviridae virus.

17. The method according to claim 15, wherein the Coronaviridae virus is the SARS virus.

22. The method according to claim 1, which is a method for treating or prophylaxis of infection by a Coronaviridae virus.

24. The method according to claim 22, wherein the Coronaviridae virus is the SARS virus.

29. The method according to claim 1, which is a method for treating or prophylaxis of an illness due to a Coronaviridae virus.

30. The method according to claim 29, wherein the illness is SARS.

16. (canceled)

18-21. -21. (canceled)

23. (canceled)

25-28. -28. (canceled)

31-44. -44. (canceled)