PYRIMIDINE NUCLEOSIDES AND THEIR MONOPHOSPHATE PRODRUGS FOR TREATMENT OF VIRAL INFECTIONS AND CANCER

• US 20140235566A1
• Filed: 10/29/2013
• Published: 08/21/2014
• Est. Priority Date: 10/29/2012
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: RFS Pharma, LLC (Cocrystal Pharma, Inc.), Emory University
• Inventors: Amblard, Franck, Coats, Steven J., Schinazi, Raymond F.
• Granted Patent: US 9,809,616 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic 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 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate

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, cytomegalovirus (CMV), herpes viruses (HSV-1, HSV-2), Dengue virus, Yellow fever, or HBV in human patients or other animal hosts. The compounds are certain N⁴-hydroxycytidine nucleosides derivatives, modified monophosphate and phosphonates prodrugs analogs, 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, cytomegalovirus (CMV), herpes viruses (HSV-1, HSV-2), Dengue virus, Yellow fever, and HBV.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein each R¹ is, independently, C_1-20 alkyl, the carbon chain derived from a fatty alcohol or C_1-20 alkyl substituted with a C₁-C₆ alkyl, alkoxy, di(C₁-C₆ alkyl)-amino, fluoro, C_3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;

wherein the substituents are C_1-6 alkyl, or C_1-6 alkyl substituted with a C₁-C₆ alkyl, C₁-C₆ alkoxy, di(C₁-C₆ alkyl)-amino, fluoro, or C_3-10 cycloalkyl.

3. The compound of claim 1, wherein Sugar is ribose or a modified ribose of the general Formula (II):

4. The compound of claim 3, wherein R^6′

is independently selected from the group consisting of NHOH, NHNH₂, N₃, C(O)NH₂, C(S)NH₂, C(O)OR, R, OR, SR, SSR, NHR, and NR₂, and wherein R is independently a C₁-C₆ alkyl, C_2-6 alkenyl, C_2-6alkynyl, C_3-6 cycloalkyl, (C₃-C₆ cycloalkyl) aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above in claim 1.

5. The compound of claim 3, wherein R^7′

is independently selected from the group consisting of H, F, Cl, Br, I, N₃, C(O)OH, CN, CH₂OH, C(O)NH₂, C(S)NH₂, C(O)OR, and R, and wherein R is independently a C₁-C₆ alkyl, C_2-6 alkenyl, C_2-6alkynyl, C_3-6 cycloalkyl, (C₃-C₆ cycloalkyl) aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above in claim 1.

6. The compound of claim 1, wherein Sugar is ribose or modified ribose of the general Formulas (III) or (IV):

7. The compound of claim 6, wherein R^7′

is independently selected from the group consisting of H, F, Cl, Br, I, N₃, C(O)OH, CN, CH₂OH, C(O)NH₂, C(S)NH₂, C(O)OR, and R.

8. The compound of claim 1, wherein Sugar is ribose or modified ribose of the general formula (V):

9. The compound of claim 8, wherein R^7′

is, independently, selected from the group consisting of H, F, Cl, Br, I, N₃, C(O)OH, CN, CH₂OH, C(O)NH₂, C(S)NH₂, C(O)OR, and R, wherein R is independently C₁-C₆ alkyl, C_2-6 alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above in connection with Formulas I, II, III and IV.

10. The compound of claim 8, wherein R⁵ and R^6′

are independently selected from the group consisting of NHOH, NHNH₂, N₃, C(O)NH₂, C(S)NH₂, C(O)OR, R, OR, SR, SSR, NHR, and NR₂.

11. The compound of claim 8, wherein when A is O or CH₂, D is H or acyl, W is CH₂, R^4′

and R^7′

are H then, R^5′

and R^6′

cannot be H, halogen, OH, SH, OCH₃, SCH₃, NH₂, NHCH₃, CH₃, CH═

CH₂, CN, CH₂NH₂, CH₂OH, or COOH.

12. The compound of claim 1, wherein Sugar is a modified ribose of the general Formula (VI):

13. The compound of claim 12, wherein R^7′

is, independently, selected from the group consisting of H, F, Cl, Br, I, N₃, C(O)OH, CN, CH₂OH, C(O)NH₂, C(S)NH₂, C(O)OR, and R.

14. The compound of claim 1, wherein Sugar is a dioxolane, an oxathiolane, or a dithiolane of the general Formulas (VII), (VIII), (IX), and (X):

15. The compound of claim 1, wherein Sugar is a dioxolane, oxathiolane, or dithiolane of the general formulas (XI), (XII), (XIII), and (XIV):

16. The compound of claim 1, wherein Sugar is a phosphonylmethoxyalkyl of the general Formula (XV):

17. The compound of claim 1, wherein Sugar is of the general Formulas (XVI) or (XVII):

18. The compound of claim 1, wherein Sugar is a modified ribose of the general Formula (XVIII)

19. The compound of claim 18, wherein R^6′

is independently selected from the group consisting of NHOH, NHNH₂, N₃, C(O)NH₂, C(S)NH₂, C(O)OR, R, OR, SR, SSR, NHR, and NR₂.

20. The compound of claim 1, wherein Sugar is a modified ribose of the general formulas (XIX):

21. The compound of claim 1, wherein Sugar has one of the Formulas (XX), (XXI), or (XXII):

22. The compound of claim 1, wherein Sugar has of one of the Formulas (XXIII) or (XXIV):

23. The compound of claim 1, wherein Sugar has one of the Formulas (XXV) or (XXVI):

26. The compound of claim 1, wherein the compounds are described herein can be in the form of the β

-L- or β

-D-configuration, or a mixture thereof, including a racemic mixture thereof.

27. The compound of claim 1, wherein when the phosphorous portion of the compound described herein contains a chiral center, such chiral center can be in the form of the R_p- or S_p-configuration or a mixture thereof, including a racemic mixture thereof.

28. 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.

29. The method of claim 28, 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.

30. The method of claim 28, wherein the compound is administered in combination with another anti-HIV agent.

31. A method for treating a host infected with HBV or 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.

32. The method of claim 31, wherein the compound is administered in combination with another anti-HBV agent.

33. 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.

34. The method of claim 33, wherein the compound is administered in combination with another anti-Norovirus or anti-Saporovirus agent.

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

36. The method of claim 35, wherein the compound is administered in combination with another anti-Norovirus or anti-Saporovirus agent.

37. 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.

38. The method of claim 37, wherein the compound is administered in combination with another anti-HSV-1 AND HSV-2 agent.

39. A method for treating a host with cancer, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

40. The method of claim 39, wherein the compound is administered in combination with another anti-cancer agent.

41. The method of claim 28, wherein the compounds are converted in a biological system to a mixture of compounds comprising mixture C or D of 4-NHOH, 4-NH₂ and 4-OH pyrimidine triphosphates:

24. A compound of one of the following formulas:

25. A compound of the formula: