Phosphonates with reduced toxicity for treatment of viral infections

Patent metadata

Field	Value
Publication number	US-9475832-B2
Application number	US-201414499865-A
Country	US
Kind code	B2
Filing date	Sep 29, 2014
Priority date	Apr 14, 2010
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

There are provided, inter alia, acyclic nucleoside phosphonate compounds having reduced toxicity and enhanced antiviral activity, and pharmaceutically accepted salts and solvates thereof. There are also provided methods of using the disclosed compounds for inhibiting viral RNA-dependent RNA polymerase, inhibiting viral reverse transcriptase, inhibiting replication of virus, including hepatitis C virus or a human retrovirus, and treating a subject infected with a virus, including hepatitis C virus or a human retrovirus.

First claim

What is claimed is:

1. A method of inhibiting an HCV RNA-dependent RNA polymerase comprising contacting a cell which includes an HCV RNA-dependent RNA polymerase with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting the viral RNA-dependent RNA polymerase; wherein the compound of Formula (I) has the structure:

wherein
B N is a substituted or unsubstituted nucleobase;
L 1 is a bond or —O—;
R 1 is halogen, —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
provided that, if L 1 is a bond, then R 1 is halogen, and
if L 1 is —O—, then R 1 is —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
R 2 is -L 2 -O—R 3   (II),

wherein L 2 is a substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted arylene; and
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

2. The method of claim 1 , wherein B N is unsubstituted adenine, substituted adenine, unsubstituted thymine, substituted thymine, unsubstituted guanine, substituted guanine, unsubstituted cytosine, substituted cytosine, unsubstituted uracil, substituted uracil, 2,6-diaminopurine, 6-methoxypurine, or 6-O-methylguanine.

3. The method of claim 2 , wherein L 1 is O; and R 1 is —CF 3 , unsubstituted alkyl, unsubstituted cycloalkyl or unsubstituted aryl.

4. The method of claim 2 , wherein L 1 is a bond; and R 1 is a halogen.

5. The method of claim 2 , wherein R 2 is octadecyloxyethyl, hexadecyloxyethyl, hexadecyloxypropyl, 15-methyl-hexadecyloxypropyl, 15-methyl-hexadecyloxyethyl, 14-methyl-tetradecyloxypropyl, 14-methyl-tetradecyloxyethyl, 14-cyclopropyl-tetradecyloxypropyl, 14-cyclopropyl-tetradecyloxyethyl or 1-O-octadecyl-2-O-benzyl-sn-glyceryl.

6. The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is:

7. A method of inhibiting a viral reverse transcriptase comprising contacting a cell which includes a viral reverse transcriptase with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting the viral reverse transcriptase;
wherein said viral reverse transcriptase is selected from the group consisting of HIV and hepatitis B virus (HBV);
wherein the compound of Formula (I) has the structure:

wherein
B N is a substituted or unsubstituted nucleobase;
L 1 is a bond or —O—;
R 1 is halogen, —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
provided that, if L 1 is a bond, then R 1 is halogen, and
if L 1 is —O—, then R 1 is —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
R 2 is -L 2 -O—R 3   (II),

wherein L 2 is a substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted arylene; and
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

8. A method of treating a subject infected with a virus selected from the group consisting of HCV and HIV, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, thereby treating the subject; wherein the compound of Formula (I) has the structure:

wherein
B N is a substituted or unsubstituted nucleobase;
L 1 is a bond or —O—;
R 1 is halogen, —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
provided that, if L 1 is a bond, then R 1 is halogen, and
if L 1 is —O—, then R 1 is —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
R 2 is -L 2 -O—R 3   (II),

wherein L 2 is a substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted arylene; and
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

9. The method of claim 8 , wherein B N is unsubstituted adenine, substituted adenine, unsubstituted thymine, substituted thymine, unsubstituted guanine, substituted guanine, unsubstituted cytosine, substituted cytosine, unsubstituted uracil, substituted uracil, 2,6-diaminopurine, 6-methoxypurine, or 6-O-methyl guanine.

10. The method of claim 9 , wherein L 1 is O; and R 1 is —CF 3 , unsubstituted alkyl, unsubstituted cycloalkyl or unsubstituted aryl.

11. The method of claim 9 , wherein L 1 is a bond; and R 1 is a halogen.

12. The method of claim 9 , wherein R 2 is octadecyloxyethyl, hexadecyloxyethyl, hexadecyloxypropyl, 15-methyl-hexadecyloxypropyl, 15-methyl-hexadecyloxyethyl, 14-methyl-tetradecyloxypropyl, 14-methyl-tetradecyloxyethyl, 14-cyclopropyl-tetradecyloxypropyl, 14-cyclopropyl-tetradecyloxyethyl or 1-O-octadecyl-2-O-benzyl-sn-glyceryl.

13. The method of claim 8 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is:

Assignees

• The Regents Of The Univ Of California A California Corp
• Univ California

Inventors

• Hostetler Karl Y
• Beadle James R
• Valiaeva Nadejda

Classifications

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• A61P31/18

  for HIV · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07F9/6512

  having the nitrogen atoms in positions 1 and 3 · CPC title