Nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases

• US 7,388,002 B2
• Filed: 11/09/2005
• Issued: 06/17/2008
• Est. Priority Date: 11/14/2001
• Status: Expired due to Term

• Current Assignee: Biocryst Pharmaceuticals Incorporated
• Original Assignee: Biocryst Pharmaceuticals Incorporated
• Inventors: El-Kattan, Yahya, Chand, Pooran, Babu, Yarlagadda S., Wu, Minwan
• Primary Examiner(s): Berch; Mark L
• Application Number:
  US11/269,819
• Publication Number:
  US 20060122391A1
• Time in Patent Office: 951 Days
• Field of Search: 514/234.2, 514/263.2, 514/263.22, 514/263.23, 514/263.38, 514/263.4, 514/81, 544/276, 544/277, 544/244, 544/265, 544/118
• US Class Current: 514/81
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 36/28 Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61P 31/14 for RNA viruses
• 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

Compounds represented by the formula:

• A is (CH₂)_nR₂, —CH═CH₂, CH₂—CH═CH₂, O(CH₂)_nR₂, CH(OH)CH₃, CH(OH)CH₂OH, CH₂—CH(OH)CH₃, CH₂CH(OH)CH₂OH, or CH(OH)CH(OH)CH₃,
• R,R₁ individually is H, NH₂OH, Cl, Br, I, aryl, substituted aryl, heterocycle, NR₃R₄, OR₃ or SR₃,
• R₂ is H, OH, F, N₃, NH₂, CO₂H, SH, alkyl, substituted alkyl, S-alkyl, O-acyl, CONH₂, or CONH-alkyl,
• n is 1-3,
• y is O, S or NH,
• W is O or S,
• Z, Z′ individually is OR₃, OR₄, O(CH₂)_m—O—(CH₂)_xCH₃, NH—CH(alkyl)CO₂R₃, alkyl, substituted alkyl, OCH₂CH₂S—C(O)CH₃, OCH₂CH₂S—C(O)CH(CH₃)₂, OCH₂CH₂S—C(O)C(CH₃)₃, OCH₂CH₂—SC(O)aryl, OCH₂CH₂—S—S—OCH₂CH₂OH, OCH₂OC(O)C(CH₃)₃, OCH₂—O—C(O)OCH(CH₃)₂, or OCH₂—O—C(O)CH(CH₃)₂
• R₃, R₄ individually is H, alkyl, substituted alkyl, aryl, or substituted aryl;

Both R₃ and R₄ can form a monocyclic ring of 4-7 atoms with N or optionally a further heteroatom in the ring;

• m is 1-3,
• x is 0-19;
  and pharmaceutically acceptable salts thereof and prodrugs thereof are provided.

Claims

1. A compound represented by the formula:

2. The compound according to claim 1 represented by the formula:

3. The compound according to claim 1 represented by the formula:

4. The compound according to claim 2 represented by the formula:

5. The compound according to claim 3 represented by the formula:

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

10. A method for inhibiting HCV polymerase in a patient by administering to the patient at least one compound according to claim 1.

11. A method for treating a patient suffering from HCV which comprises administering to said patient an effective amount of at least one compound according to claim 1.

12. A method for inhibiting in a patient in need thereof a HCV viral polymerase which comprises administering to said patient an effective amount of at least one compound according to claim 1 and at least one further therapeutic agent from the group consisting of interferon (IFN), interferon α

-2a, interferon α

-2b, consensus interferon (CIFN), ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), and glycyrrhizin.

13. A method for treating a patient suffering from a HCV viral infection which comprises administering to the patient an effective amount of at least one compound according to claim 1 and at least one further therapeutic agent chosen from interferon (IFN), interferon α

-2a, interferon α

-2b, consensus interferon (CIFN), ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), and glycyrrhizin.

14. A pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.

6. The compound represented by the formula:

7. The compound according to claim 6 represented by the formula:

15. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier.

8. The compound represented by the formula:

16. A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.