Nucleotide mimics and their prodrugs

• US 7,807,653 B2
• Filed: 06/14/2007
• Issued: 10/05/2010
• Est. Priority Date: 02/28/2002
• Status: Expired due to Fees

• Current Assignee: Biota Scientific Management Pty Limited (Vaxart, Inc.)
• Original Assignee: Biota Scientific Management Pty Limited (Vaxart, Inc.)
• Inventors: Jin, Yi, Ariza, Maria Eugenia, Prhavc, Marija, Fagan, Patrick C., Rajwanshi, Vivek K., Bruice, Thomas W., Tucker, Kathleen D., Boyle, Nicholas A., Cook, Phillip D., Brooks, Jennifer L., Wang, Guangyi, Leeds, Janet M.
• Primary Examiner(s): OLSON, ERIC
• Application Number:
  US11/818,666
• Publication Number:
  US 20070265224A1
• Time in Patent Office: 1,209 Days
• Field of Search: None
• US Class Current: 514/47
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.

Claims

1. A compound of Formula (V) which may be a D- or L-nucleotide:

2. A compound of Formula (VI) which may be a D- or L-nucleotide:

3. The compound defined in claim 2

wherein X² is O;

and

wherein X⁷ is SH, NH₂, ⁻

BH₃M⁺, alkyl, aryl, alkylamino, or arylamino.

4. The compound defined in claim 2

wherein X² is O;

and

wherein X⁷ is selected from the group consisting of SH, NH₂, ⁻

BH₃M⁺, R, and NHR.

5. A compound of Formula (VI) which may be a D- or L-nucleotide:

6. A compound of Formula (VI) which may be

a D- or L-nucleotide:

8. The compound defined in claim 6 wherein at least one of X⁹ and X¹⁰ is 1,2-O-dialkylglyceryloxy.

7. A compound of Formula (VI) which may be a D- or L-nucleotide:

9. A compound of Formula (VI) which may be a D- or L-nucleotide:

10. A compound of Formula (VI) which may be a D- or L-nucleotide:

11. A compound of Formula (VI) which may be a D- or L-nucleotide:

12. A compound of Formula (VI) which may be a D- or L-nucleotide:

13. A compound of Formula (VI) which may be

a D- or L-nucleotide:

14. A compound of Formula (VI) which may be a D- or L-nucleotide:

15. A compound of Formula (VI) which may be a D- or L-nucleotide:

16. A compound of Formula (VI) which may be a D- or L-nucleotide:

17. A compound of Formula (XVI):

18. A compound of Formula (XVI):

19. The compound defined in claim 18 where Nu is selected from the group consisting of:

adenosine,

guanosine,

2′

-deoxyadenosine,

2′

-deoxyguanosine,

inosine,

9-(β

-D-arabinofuranosyl)adenine,

9-(β

-D-arabinofuranosyl)guanine,

9-(β

-D-arabinofuranosyl)hypoxanthine,

3′

-azido-2′

,3′

-dideoxyadenosine,

3′

-azido-2′

,3′

-dideoxyguanosine,

3′

-azido-2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyinosine,

2′

,3′

-dideoxyadenosine,

2′

,3′

-dideoxyguanosine,

9-(2,3-dideoxy-1-β

-D-ribofuranosyl)-2,6-diaminopurine,

2′

,3′

-didehydro-2′

,3′

-dideoxyadenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyguanosine,

2′

,3′

-didehydro-2′

,3′

-dideoxyinosine,

3-deazaadenosine,

3-deazaguanosine,

3-deazainosine,

7-deazaadenosine,

7-deazaguanosine,

7-deazainosine,

9-(β

-D-ribofuranosyl)-6-thiopurine,

6-methylthio-9-(β

-D-ribofuranosyl)purine,

2-amino-9-(β

-D-ribofuranosyl)-6-thiopurine,

2-amino-6-methylthio-9-(β

-D-ribofuranosyl)purine,

2′

-C-methyladenosine,

2′

-C-methylguanosine,

2′

-C-methylinosine,

2′

-deoxy-2′

-fluoroadenosine,

2′

-deoxy-2′

-fluoroguanosine,

2′

-deoxy-2′

-fluoroinosine,

2′

-deoxy-2′

-fluoroarabinoadenosine,

2′

-deoxy-2′

-fluoroarabinoguanosine,

2′

-deoxy-2′

-fluoroarabinoinosine,

2′

-O-methyladenosine,

2′

-O-methylguanosine,

2′

-O-methylinosine,

2′

-C-ethynylguanosine,

2′

-C-ethynylinosine,

3′

-C-ethynyladenosine,

3′

-C-ethynylguanosine,

3′

-C-ethynylinosine,

3′

-deoxyadenosine,

3′

-deoxyguanosine,

3′

-deoxyinosine,

4′

-C-ethynyladenosine,

4′

-C-ethynylguanosine,

4′

-C-ethynylinosine,

4′

-C-methyladenosine,

4′

-C-methylguanosine,

4′

-C-methylinosine,

2′

-C-methyl-7-deazaadenosine,

2′

-C-methyl-7-deazaguanosine,

2′

-C-methyl-3-deazaadenosine,

2′

-C-methyl-3-deazaguanosine,

2′

-O-methyl-7-deazaadenosine,

2′

-O-methyl-7-deazaguanosine,

2′

-O-methyl-3-deazaadenosine,

2′

-O-methyl-3-deazaguanosine,

2′

-C-methyl-2-chloroadenosine,

2′

-deoxy-7-deazaadenosine,

2′

-deoxy-3-deazaadenosine,

2′

-deoxy-7-deazaguanosine,

2′

-deoxy-3-deazaguanosine,

2′

-deoxy-2-chloroadenosine,

2′

-deoxy-2-fluoroadenosine,

3′

-deoxy-7-deazaadenosine,

3′

-deoxy-7-deazaguanosine,

3′

-deoxy-3-deazaadenosine,

3′

-deoxy-3-deazaguanosine,

3′

-deoxy-2-chloroadenosine,

2′

,3′

-dideoxy-7-deazaadenosine,

2′

,3′

-dideoxy-7-deazaguanosine,

2′

,3′

-dideoxy-3-deazaadenosine,

2′

,3′

-dideoxy-3-deazaguanosine,

2′

,3′

-dideoxy-2-chloroadenosine,

2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-dideoxy-β

-L-guanosine,

2′

-deoxy-β

-L-adenosine,

2′

-deoxy-β

-L-guanosine,

2′

-deoxy-β

-L-inosine,

β

-L-adenosine,

β

-L-guanosine,

β

-L-inosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-adenosine,

2′

,3′

-didehydro-2′

,3′

-dideoxy-β

-L-guanosine,

9-(β

-D-arabinofuranosyl)-2-fluoroadenine,

2′

,3′

-dideoxy-3′

-fluoroguanosine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(±

)-(1α

,2β

,3α

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine,

(±

)-(1β

,2α

,3β

)-9-[2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine,

(1R,3S,4R)-9-(3-hydroxy-4-hydroxymethylcyclopent-1-yl)guanine,

(1S,2R,4R)-9-(1-hydroxy-2-hydroxymethylcyclopent-4-yl)guanine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)-2,6-diaminopurine,

(2R,4R)-9-(2-hydroxymethyl-1,3-dioxolan-4-yl)guanine,

(1R,2S,4S)-9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-4-yl]guanine, and

(1S,3R,4S)-9-(3-hydroxy-4-hydroxymethyl-5-methylenecyclopent-1-yl]guanine.

20. A compound of Formula (XVI):

21. A compound of Formula (XVI):

22. A method for the treatment of HIV infection comprising administering a therapeutically effective amount of a compound of Formula (I) which may be a D- or L-nucleotide:

23. A method for the treatment of lymphoblastic leukemia comprising administering a therapeutically effective amount of a compound of Formula (I) which may be a D- or L-nucleotide:

24. A compound of Formula (XVI):

25. The compound defined in claim 24,

wherein at least one of X⁰, X⁵ or X⁶ is CF₂.

26. The compound defined in claim 24,

wherein X⁶ is CF₂ or CCl₂.

27. The compound defined in claim 24,

wherein X⁷ is ⁻

BH₃M⁺.

28. A compound of Formula (VI) which is a D-nucleotide: