Phosphonates with reduced toxicity for treatment of viral infections

• US 8,846,643 B2
• Filed: 10/11/2012
• Issued: 09/30/2014
• Est. Priority Date: 04/14/2010
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hostetler, Karl Y., Beadle, James R., Valiaeva, Nadejda
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US13/649,671
• Publication Number:
  US 20130029940A1
• Time in Patent Office: 719 Days
• Field of Search: None
• US Class Current: 514/81
• 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 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A compound having the structure of Formula (I):

2. The compound 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 compound of claim 1, with structure of Formula (Ia):

4. The compound of claim 1, wherein R¹ is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl.

5. The compound of claim 1, wherein R¹ is unsubstituted C₁-C₁₀ alkyl.

6. The compound of claim 5, wherein R¹ is methyl, ethyl or isopropyl.

7. The compound of claim 1, wherein R¹ is unsubstituted cycloalkyl.

8. The compound of claim 1, wherein R¹ is unsubstituted aryl.

9. The compound of claim 8, wherein R¹ is phenyl.

10. The compound of claim 1, wherein R¹ is unsubstituted alkyl, substituted cycloalkyl, or substituted aryl.

11. The compound of claim 1, with structure of Formula (Ib):

12. The compound of claim 11, wherein R¹ is fluoro.

13. The compound of claim 1, with the structure of Formulae (Ia1) to (Ia7):

14. The compound of claim 1, wherein R² 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.

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

17. A method of inhibiting a viral reverse transcriptase comprising contacting a cell comprising a viral reverse transcriptase with an effective amount of a compound of claim 1, thereby inhibiting said viral reverse transcriptase, wherein said viral reverse transcriptase is an HIV reverse transcriptase.

15. A compound with structure: