IP Library › Granted Patent US 7,323,453

Granted Patent B2

US 7,323,453 · App. 10/504,445 · Granted Jan 29, 2008

Methods of inhibiting orthopoxvirus replication with nucleoside compounds

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Quick Facts

Patent No.: US 7,323,453
App. No.: 10/504,445
Granted: Jan 29, 2008
Kind: B2

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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 (173)

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:

or a pharmaceutically acceptable salt thereof; wherein

A is N or C-R 9 ;

R 1 is C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, or one to three fluorine atoms;

R 2 is amino, fluorine, hydroxy, C 1-10 alkylcarbonyloxy, mercapto, or C 1-4 alkoxy;

R 3 and R 4 are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, C 1-16 alkylcarbonyloxy, C 2-18 alkenylcarbonyloxy, C 1-10 alkyloxycarbonyloxy, C 3-6 cycloalkylcarbonyloxy, C 3-6 cycloalkyloxycarbonyloxy, mercapto, amino, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, or one to three fluorine atoms;

R 5 is hydrogen, C 1-6 alkylcarbonyl, C 2-18 alkenylcarbonyl, C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or P(O)R 13 R 14 ;

R 6 and R 7 are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl;

R 8 is hydrogen, C 1-4 alkyl, C 2-4 alkynyl, halogen, cyano, carboxy, C 1-4 alkyloxycarbonyl, azido, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;

R 9 is hydrogen, cyano, nitro, NHCONH 2 , CONR 12 R 12 , CSNR 12 R 12 , COOR 12 , C(═NH)NH 2 , hydroxy, C 1-3 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogen, or C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;

R 10 and R 11 are each independently hydrogen, hydroxy, mercapto, halogen, C 1-4 alkoxy, C 1-4 alkylthio, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, di(C 3-6 cycloalkyl)amino, phenyl-C 1-2 alkylamino, C 1-4 acylamino, C 1-8 alkylcarbonyloxy, or OCH(C 1-4 alkyl)O(C═O)C 1-4 alkyl;

each R 12 is independently hydrogen or C 1-6 alkyl; and

R 13 and R 14 are each independently hydroxy, OCH 2 CH 2 SC(═O)C 1-4 alkyl, OCH 2 O(C═O)OC 1-4 alkyl, NHCHMeCO 2 Me, OCH(C 1-4 alkyl)O(C═O)C 1-4 alkyl,

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:

or a pharmaceutically acceptable salt thereof; wherein

A is N or C—R 9 ;

R 1 is C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-3 alkoxy, C 1-3 alkylthio, or one to three fluorine atoms;

R 2 is hydroxy, C 1-16 alkylcarbonyloxy, fluoro, or C 1-3 alkoxy;

R 3 is hydrogen, halogen, hydroxy, C 1-16 alkylcarbonyloxy, amino, or C 1-3 alkoxy;

R 5 is hydrogen, C 1-16 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or PO 3 H 2 ;

R 8 is hydrogen, amino, or C 1-4 alkylamino;

R 9 is hydrogen, cyano, methyl, halogen, or CONH 2 ; and

R 10 and R 11 are each independently hydrogen, halogen, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, or C 3-6 cycloalkylamino.

4. The method of claim 3 wherein

R 1 is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R 2 is hydroxy, C 1-16 alkylcarbonyloxy, fluoro, or methoxy;

R 3 is hydrogen, fluoro, hydroxy, C 1-16 alkylcarbonyloxy, amino, or methoxy;

R 5 is hydrogen, C 1-16 alkylcarbonyl, or P 3 O 9 H 4 ;

R 8 is hydrogen or amino;

R 9 is hydrogen, cyano, methyl, halogen, or CONH 2 ; and

R 10 and R 11 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:

or a pharmaceutically acceptable salt thereof; wherein

A is N or C—R 9 ;

R 1 is C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-3 alkoxy, C 1-3 alkylthio, or one to three fluorine atoms;

R 2 is hydroxy, C 1-16 alkylcarbonyloxy, fluoro, or C 1-3 alkoxy;

R 3 is hydrogen, halogen, hydroxy, C 1-16 alkylcarbonyloxy, amino, or C 1-3 alkoxy;

R 5 is hydrogen, C 1-16 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or PO 3 H 2 ;

R 8 is hydrogen, amino, or C 1-4 alkylamino;

R 9 is hydrogen, cyano, methyl, halogen, or CONH 2 ; and

R 10 and R 11 are each independently hydrogen, halogen, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, or C 3-6 cycloalkylamino.

13. The method of claim 12 wherein

R 1 is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;

R 2 is hydroxy, C 1-6 alkylcarbonyloxy, fluoro, or methoxy;

R 3 is hydrogen, fluoro, hydroxy, C 1-16 alkylcarbonyloxy, amino, or methoxy;

R 5 is hydrogen, C 1-16 alkylcarbonyl, or P 3 O 9 H 4 ;

R 8 is hydrogen or amino;

R 9 is hydrogen, cyano, methyl, halogen, or CONH 2 ; and

R 10 and R 11 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: