Nucleoside cyclic phosphoramidates for the treatment of RNA-dependent RNA viral infection

• US 8,148,349 B2
• Filed: 12/14/2007
• Issued: 04/03/2012
• Est. Priority Date: 12/20/2006
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Istituto Di Ricerche Di Biologia Molecolare P Angeletti SPA (Merck & Co., Inc.), Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Meppen, Malte, Narjes, Frank, Pacini, Barbara, Gardelli, Cristina, Durette, Philippe L.
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US12/519,038
• Publication Number:
  US 20100022468A1
• Time in Patent Office: 1,572 Days
• Field of Search: None
• US Class Current: 514/51
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

The present invention provides nucleoside cyclic phosphoramidates of formula (I), pharmaceutical compositions comprising the compounds of formula (I) and methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection using the compounds of formula (I).

Claims

1. A compound of the structural formula I:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-A:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B1:

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein

R⁶ is hydrogen, C_1-16 alkyl, C_2-20 alkenyl, (CH₂)_nC_3-6 cycloalkyl, phenyl, benzyl, or adamantyl;

wherein alkyl, alkenyl, cycloalkyl, and adamantyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, and C_1-4 alkoxy; and

wherein phenyl and benzyl are optionally substituted with one to three substituents independently selected from halogen, hydroxy, cyano, C_1-4 alkoxy, trifluoromethyl, and trifluoromethoxy; and

R⁹ is hydrogen, C_1-8 alkylcarbonyl, or C_1-8 alkyloxycarbonyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl or fluoromethyl, and R² is hydroxy.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl or fluoromethyl, and R² is fluoro.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen and R⁴ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, 2-methyl-1-propyl, hydroxymethyl, fluoromethyl, mercaptomethyl, carboxymethyl, carbamoylmethyl, 1-hydroxyethyl, 2-carboxyethyl, 2-carbamoylethyl, 2-methylthioethyl, 4-amino-1-butyl, 3-amino-1-propyl, 3-guanidino-1-propyl, 1H-imidazol-4-ylmethyl, phenyl, 4-hydroxybenzyl, and 1H-indol-3-ylmethyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is C_1-8 alkyl, cyclohexyl, cyclopentyl, cyclohexylmethyl, 2-cyclohexylethyl, or 3-cyclohexyl-n-propyl, each of which is optionally substituted with one to three substituents independently selected from fluorine, hydroxy, and C_1-6 alkoxy.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R⁶ is ethyl, butyl, or heptyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is methyl, R⁵ is hydrogen, and R⁶ is ethyl, butyl, or heptyl.

12. The compound of claim 1, which is a compound of Formula II:

13. The compound of claim 1, which is a compound of Formula III-A:

14. The compound of claim 13, which is a compound of Formula III-B:

15. The compound of claim 1, which is selected from the group consisting of:

n-butyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4-H-furo[3,2-d][1,2,3]dioxaphosphinin-2-yl]amino}propanoate;

ethyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4-H-furo[3,2-d][1,2,3]dioxaphosphinin-2-yl]amino}propanoate;

n-heptyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4-H-furo[3,2-d][1,2,3]dioxaphosphinin-2-yl]amino}propanoate;

tert-butyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

n-butyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

ethyl (2S)-2-{[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]dioxaphosphinin-2-yl]amino}butanoate;

ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-leucinate;

ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-norvalinate;

cyclopentyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2oxidotetrahydro-4H-furo[3,2-d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

n-heptyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2oxidotetrahydro-4Hfuro[3,2d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

cyclohexyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2oxidotetrahydro-4Hfuro[3,2d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

isopentyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2d][1,3,2]-dioxaphosphinin-2-yl]-L-alaninate;

3-methoxypropyl N[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

2-ethylbutyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

2-propylpentyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

2-(hexyloxy)ethyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

cycloheptyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

3-cyclohexylpropyl N-[(4aR,6R,7R,7aR)-6-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl]-L-alaninate;

ethyl (2S)-2-({(4aR,6R,7R,7aR)-7-hydroxy-7-methyl-2-oxido-6-[2-oxo-4-[(2-propylpentanoyl)amino]pyrimidin-1(2H)-yl]tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}amino)butanoate;

ethyl N-{(4aR,6R,7R,7aR)-7-hydroxy-7-methyl-2-oxido-6-[2-oxo-4-[(2-propylpentanoyl)amino]pyrimidin-1(2H)-yl]tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}-L-alaninate;

n-heptyl N-{(4aR,6R,7R,7aR)-7-hydroxy-7-methyl-6-[4-[(1-methylene-2-propylpentyl)amino]-2-oxopyrimidin-1(2H)-yl]-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}-L-alaninate; and

n-heptyl N-{(4aR,6R,7R,7aR)-6-[4-({[3-(dimethylamino)propoxy]carbonyl}amino)-2-oxopyrimidin-1(2H)-yl]-7-hydroxy-7-methyl-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl}-L-alaninate;

and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method for the treatment of hepatitis C virus infection in a mammal in need thereof, which comprises administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to the mammal.