Methods of inhibiting orthopoxvirus replication with nucleoside compounds

• US 20050164960A1
• Filed: 02/07/2003
• Published: 07/28/2005
• Est. Priority Date: 02/13/2002
• Status: Active Grant

• Current Assignee: ISIS Pharmaceuticals Incorporated, Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Olsen, David B., Bera, Sanjib, Eldrup, Anne B., LaFemina, Robert L.
• Granted Patent: US 7,323,453 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides methods of inhibiting orthopoxvirus replication and/or treating orthopoxvirus infection with certain nucleoside compounds and derivatives thereof. These compounds are particularly useful as inhibitors of vaccinia virus and variola virus replication and/or for the treatment of vaccinia virus and variola virus infection. The nucleoside compounds may be administered alone or in combination with other agents active against orthopoxvirus infection, in particular against vaccinia virus or variola virus infection. Another aspect of the present invention provides for the use of such nucleoside compounds in the manufacture of a medicament for the inhibition of orthopoxvirus replication and/or for the treatment of orthopoxvirus infection. Yet a further aspect of the present invention provides such nucleoside compounds for use as a medicament for the inhibition of orthopoxvirus replication and/or for the treatment of orthopoxvirus infection.

Claims

1. A method of inhibiting orthopoxvirus replication comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula I:

2. A method of treating orthopoxvirus infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of claim 1.

3. The method of claim 1 wherein the compound is of structural formula II:

4. The method of claim 3 wherein

R¹ is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R² is hydroxy, C_1-16 alkylcarbonyloxy, fluoro, or methoxy;

R³ is hydrogen, fluoro, hydroxy, C_1-16 alkylcarbonyloxy, amino, or methoxy;

R⁵ is hydrogen, C_1-16 alkylcarbonyl, or P₃O₉H₄;

R⁸ is hydrogen or amino;

R⁹ is hydrogen, cyano, methyl, halogen, or CONH₂; and

R¹⁰ and R¹¹ are each independently hydrogen, halogen, hydroxy, amino, C_1-4 alkylamino, di(C_1-4 alkyl)amino, or C_3-6 cycloalkylamino.

5. The method of claim 4 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,

4-methylamino-7-(2-C-methyl-β

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

4-dimethylamino-7-(2-C-methyl-β

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

4-cyclopropylamino-7-(2-C-methyl-β

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

4-amino-7-(2-C-hydroxymethyl-β

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

4-amino-7-(2-C-fluoromethyl-β

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

4-amino-5-methyl-7-(2-C-methyl-β

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

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,

4-amino-5-bromo-7-(2-C-methyl-β

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

4-amino-5-chloro-7-(2-C-methyl-β

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

4-amino-5-fluoro-7-(2-C-methyl-β

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

2,4-diamino-7-(2-C-methyl-β

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

2-amino-7-(2-C-methyl-β

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

2-amino-4-cyclopropylamino-7-(2-C-methyl-β

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

2-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

4-amino-2-fluoro-7-(2-C-methyl-β

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

9-(2-C-methyl-β

-D-ribofuranosyl)-2-amino-6-hydroxypurine,

9-(2-C-methyl-β

-D-ribofuranosyl)-2-amino-6-cyclopropylaminopurine,

9-(2-C-methyl-β

-D-ribofuranosyl)-2,6-diaminopurine,

9-(2-C-methyl-β

-D-ribofuranosyl)-2-amino-6-methylaminopurine,

6-amino-2-fluoro-9-(2-C-methyl-β

-D-ribofuranosyl)purine,

2′

-C-methyl-adenosine,

4-amino-7-[2-C-methyl-3-O-(1-oxo-octyl)-β

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

4-amino-7-[2-C-methyl-3,5-di-O-(1-oxo-octyl)-β

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

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 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,

4-amino-7-(2-C-fluoromethyl-β

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

4-amino-5-methyl-7-(2-C-methyl-β

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

4-amino-5-bromo-7-(2-C-methyl-β

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

4-amino-5-chloro-7-(2-C-methyl-β

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

4-amino-5-fluoro-7-(2-C-methyl-β

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

4-amino-2-fluoro-7-(2-C-methyl-β

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

6-amino-2-fluoro-9-(2-C-methyl-β

-D-ribofuranosyl)purine,

2′

-C-methyl-adenosine,

4-amino-7-[2-C-methyl-3-O-(1-oxo-octyl)-β

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

4-amino-7-[2-C-methyl-3,5-di-O-(1-oxo-octyl)-β

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

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 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.

8. The method of claim 6 wherein the compound is

4-amino-7-[2-C-methyl-3-O-(1-oxo-octyl)-β

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

or a pharmaceutically acceptable salt thereof.

9. The method of claim 6 wherein the compound is

4-amino-7-(2-C-fluoromethyl-β

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

or a pharmaceutically acceptable salt thereof.

10. The method of claim 6 wherein the compound is

4-amino-7-[2-C-methyl-3,5-di-O-(1-oxo-octyl)-β

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

or a pharmaceutically acceptable salt thereof.

11. The method of claim 6 wherein the compound is

4-amino-5-fluoro-7-(2-C-methyl-β

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

or a pharmaceutically acceptable salt thereof.

12. The method of claim 2 wherein the compound is of structural formula II:

13. The method of claim 12 wherein

R¹ is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R² is hydroxy, C_1-6 alkylcarbonyloxy, fluoro, or methoxy;

R³ is hydrogen, fluoro, hydroxy, C_1-16 alkylcarbonyloxy, amino, or methoxy;

R⁵ is hydrogen, C_1-16 alkylcarbonyl, or P₃O₉H₄;

R⁸ is hydrogen or amino;

R⁹ is hydrogen, cyano, methyl, halogen, or CONH₂; and

R¹⁰ and R¹¹ are each independently hydrogen, halogen, hydroxy, amino, C_1-4 alkylamino, di(C_1-4 alkyl)amino, or C_3-6 cycloalkylamino.

14. The method of claim 13 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,

4-methylamino-7-(2-C-methyl-β

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

4-dimethylamino-7-(2-C-methyl-β

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

4-cyclopropylamino-7-(2-C-methyl-β

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

4-amino-7-(2-C-hydroxymethyl-β

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

4-amino-7-(2-C-fluoromethyl-β

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

4-amino-5-methyl-7-(2-C-methyl-β

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

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,

4-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,

4-amino-5-bromo-7-(2-C-methyl-β

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

4-amino-5-chloro-7-(2-C-methyl-β

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

4-amino-5-fluoro-7-(2-C-methyl-β

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

2,4-diamino-7-(2-C-methyl-β

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

2-amino-7-(2-C-methyl-β

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

2-amino-4-cyclopropylamino-7-(2-C-methyl-β

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

2-amino-7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

7-(2-C-methyl-β

-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,

4-amino-2-fluoro-7-(2-C-methyl-β

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

9-(2-C-methyl-β

-D-ribofuranosyl)-2-amino-6-hydroxypurine,

9-(2-C-methyl-β

-D-ribofuranosyl)-2-amino-6-cyclopropylaminopurine,

9-(2-C-methyl-β

-D-ribofuranosyl)-2,6-diaminopurine,

9-(2-C-methyl-β

-D-ribofuranosyl)-2-amino-6-methylaminopurine,

6-amino-2-fluoro-9-(2-C-methyl-β

-D-ribofuranosyl)purine,

2′

-C-methyl-adenosine,

4amino-7-[2-C-methyl-3-O-(1-oxo-octyl)-β

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

4-amino-7-[2-C-methyl-3,5-di-O-(1-oxo-octyl)-β

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

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 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,

4-amino-7-(2-C-fluoromethyl-β

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

4-amino-5-methyl-7-(2-C-methyl-β

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

4-amino-5-bromo-7-(2-C-methyl-β

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

4-amino-5-chloro-7-(2-C-methyl-β

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

4-amino-5-fluoro-7-(2-C-methyl-β

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

4-amino-2-fluoro-7-(2-C-methyl-β

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

6-amino-2-fluoro-9-(2-C-methyl-β

-D-ribofuranosyl)purine,

2′

-C-methyl-adenosine,

4-amino-7-[2-C-methyl-3-O-(1-oxo-octyl)-β

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

4-amino-7-[2-C-methyl-3,5-di-O-(1-oxo-octyl)-β

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

and the corresponding 5′

-triphosphates;

or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 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.

17. The method of claim 15 wherein the compound is

4-amino-7-[2-C-methyl-3-O-(1-oxo-octyl)-β

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

or a pharmaceutically acceptable salt thereof.

18. The method of claim 15 wherein the compound is

4-amino-7-(2-C-fluoromethyl-β

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

or a pharmaceutically acceptable salt thereof.

19. The method of claim 15 wherein the compound is

4-amino-7-[2-C-methyl-3,5-di-O-(1-oxo-octyl)-β

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

or a pharmaceutically acceptable salt thereof.

20. The method of claim 15 wherein the compound is

4-amino-5-fluoro-7-(2-C-methyl-β

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

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 wherein said orthopoxvirus replication is vaccinia virus or variola virus replication.

22. The method of claim 2 wherein said orthopoxvirus infection is vaccinia virus or variola virus infection.

23. The method of claim 22 in combination with a therapeutically effective amount of another agent active against orthopoxvirus.

24. The method of claim 23 wherein said agent active against orthopoxvirus is cidofovir, ribavirin, levovirin, or viramidine.

25. Use of a compound of claim 1 for the inhibition of orthopoxvirus replication in a mammal.

26. Use of a compound of claim 1 for the treatment of orthopoxvirus infection in a mammal.

27. The use of claim 26 wherein said orthopoxvirus infection is vaccinia virus infection or variola virus infection.

28. Use of a compound of claim 1 in the manufacture of a medicament for the inhibition of orthopoxvirus replication in a mammal.

29. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of orthopoxvirus infection in a mammal.

30. The use of claim 29 wherein said orthopoxvirus infection is vaccinia virus or variola virus infection.

31. The method of claim 8 wherein the orthopoxvirus replication is vaccinia virus or variola virus replication.

32. The method of claim 17 wherein the orthopoxvirus replication is vaccinia virus or variola virus replication.

33. A compound which is 6-amino-2-fluoro-9-(2-C-methyl-β

-D-ribofuranosyl)purine or a pharmaceutically acceptable salt thereof.