Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections

• US 8,609,627 B2
• Filed: 02/09/2010
• Issued: 12/17/2013
• Est. Priority Date: 02/06/2009
• Status: Expired due to Fees

• Current Assignee: Emory University
• Original Assignee: RFS Pharma, LLC (Cocrystal Pharma, Inc.), Emory University
• Inventors: Cho, Jong Hyun, Coats, Steven J., Schinazi, Raymond F., Zhang, Hongwang, Zhou, Longhu
• Primary Examiner(s): LEWIS, PATRICK T
• Application Number:
  US13/144,718
• Publication Number:
  US 20120040924A1
• Time in Patent Office: 1,407 Days
• Field of Search: None
• US Class Current: 514/48
• 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 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 31/7042 Compounds having saccharide radicals and heterocyclic rings
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 473/16 two nitrogen atoms
• CPC Class Codes: C07H 19/173 with 2-deoxyribosyl as the saccharide radical
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• 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

The present invention is directed to compounds, compositions and methods for treating or preventing cancer and viral infections, in particular, HIV, HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever, and HBV in human patients or other animal hosts. The compounds are certain 6-substituted purine monophosphates, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HIV-1, HIV-2, HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever, and HBV.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein R^6′

selected from the group consisting of H, F, Cl, Br, I, OH, SH, NH₂, NHOH, NHNH₂, C(O)OH, CN, C(O)NH₂, C(S)NH₂, C(O)OR, R, OR, SR, SSR, NHR, and NR₂.

3. The compounds of claim 1, wherein R⁵ is selected from the group consisting of NH₂, dimethylamine, methyl-allyl-amine, methoxy, chloro, cyclopropylamine, 5-hydroxy-pentylamine, 1,1-dimethyl-ethanolamine, and 2-methoxy-ethylamine.

4. The compounds of claim 1, wherein the compounds are in the β

-L- or β

-D configuration, or a racemic mixture thereof.

5. A method for treating a host infected with HIV-1 or HIV-2, or reducing the biological activity of an HIV-1 or HIV-2 infection in a host, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

6. The method of claim 5, wherein the HIV-1 or HIV-2 infection is caused by a virus comprising a mutation selected from the group consisting of TAM mutations and the M184V mutation.

7. The method of claim 5, wherein the compound is administered in combination with another anti-HIV agent.

8. The method of claim 7, wherein the HIV-1 or HIV-2 infection is caused by a virus comprising a mutation selected from the group consisting of TAM mutations and the M184V mutation.

9. A method for treating a host infected with HBV, or for reducing the biological activity of an HBV infection in a host, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

10. The method of claim 7, wherein the compound is administered in combination with another anti-HBV agent.

11. A method for treating a host infected with Norovirus or Saporovirus, or reducing the biological activity of an Norovirus or Saporovirus infection in a host, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

12. The method of claim 11, wherein the compound is administered in combination with another anti-Norovirus or anti-Saporovirus agent.

13. A method for treating a host infected with a Flaviviridae virus or reducing the biological activity of an infection with a Flaviviridae virus in a host, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

14. A method for treating a host infected with HSV-1 or HSV-2, or reducing the biological activity of an HSV-1 or HSV-2 infection in a host, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

15. The method of claim 10, wherein the compound is administered in combination with another anti-HSV-1 AND HSV-2 agent.

16. The compound of claim 1, wherein R¹ is selected from the group consisting of halogen, OR′

, N(R′

)₂, SR′

, OCOR′

, NHCOR′

, N(COR′

)COR′

, SCOR′

, OCOOR′

, and NHCOOR′

, and wherein each R′

is independently H, a C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more hydroxyalkyl, aminoalkyl, or alkyoxyalkyl substituents.

17. The method of claim 13, wherein the virus is selected from the group consisting of HCV, Yellow fever, Dengue, and West Nile virus.

18. A compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof, wherein the lipid is a phospholipid.