Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections

• US 20070042991A1
• Filed: 12/06/2004
• Published: 02/22/2007
• Est. Priority Date: 06/28/2002
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.), Universite Montpellier II, University of Calgary
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Sommadossi, Jean-Pierre, Gosselin, Gilles, Storer, Richard, LaColla, Paola
• Granted Patent: US 7,365,057 B2
• Time in Patent Office: Days
• US Class Current: 514/47
• 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 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/048 Pyridine radicals
• CPC Class Codes: C07H 19/056 Triazole or tetrazole radicals
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/22 : Pteridine radicals

Abstract

2′ and/or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

Claims

1. A compound of formula (XI) or (XII):

2. A method for the treatment of a host infected with a Flaviviridae virus, comprising administering an effective treatment amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claim 1.

3. The method of claim 2, wherein the virus is hepatitis C.

4. The method of claim 2, wherein the compound or pharmaceutically acceptable salt thereof, is administered in combination or alternation with a second anti-viral agent.

5. The method of claim 2 wherein the second anti-viral agent is selected from the group consisting of an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenan-threnequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

6. The method of claim 2, wherein the second ant-viral agent is an interferon.

7. The method of claim 6, wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.

8. The method of claim 2, wherein the compound or pharmaceutically acceptable salt thereof, is in the form of a dosage unit.

9. The method of claim 8, wherein the dosage unit is a tablet or capsule.

10. The method of claim 2, wherein the host is a human.

11. The compound of claim 1, in substantially pure form.

12. The method of claim 2, wherein the compound is at least 90% by weight of the β

-D-isomer.

13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13, comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof, for the treatment of a host infected with a Flaviviridae virus.

15. The pharmaceutical composition of claim 13, wherein the compound or a pharmaceutically acceptable salt thereof, is in the form of a dosage unit.

16. The pharmaceutical composition of claim 13, wherein the dosage unit contains 50 to 1000 mg of the compound.

17. The pharmaceutical composition of claim 16, wherein said dosage unit is a tablet or capsule.

18. The pharmaceutical composition of claim 13, further comprising a second anti-viral agent.

19. The pharmaceutical composition of claim 13, or pharmaceutically acceptable salt thereof, is in substantially pure form.

20. The pharmaceutical composition of claim 13, further comprising a pharmaceutically acceptable carrier suitable for systemic, topical, parenteral, inhalant or intravenous delivery.