Antiviral compounds and methods of making and using thereof

• US 9,212,177 B2
• Filed: 08/05/2010
• Issued: 12/15/2015
• Est. Priority Date: 08/05/2009
• Status: Active Grant

• Current Assignee: Versitech Limited (Government of Hong Kong Special Administrative Region)
• Original Assignee: Versitech Limited (Government of Hong Kong Special Administrative Region)
• Inventors: Kao, Yi Tsun Richard, Yang, Dan, Yuen, Kwok-Yung
• Primary Examiner(s): Pagonakis, Anna
• Application Number:
  US12/850,806
• Publication Number:
  US 20110212975A1
• Time in Patent Office: 1,958 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Compounds which exhibit antiviral activity, particularly against influenza virus, and methods of making and using thereof are described herein. In one embodiment, the compounds are heterocyclic amides containing piperazine and isozazole rings and optionally substituted with one or more substituents. The compounds can be formulated with one or more pharmaceutically acceptable excipients to form compositions suitable for enteral or parenteral administration. The compounds are preferably used to treat or prevent Influenza A infections, such as H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7.

Claims

1. A compound of formula VI:

2. The compound of claim 1, wherein A and D are nitrogen.

3. The compound of claim 1, wherein R₄ and R₁₀ are independently hydrogen or methyl.

4. The compound of claim 3, wherein R₄ is methyl and R₁₀ is hydrogen.

5. The compound of claim 3, wherein R₁₀ is a methyl group and R₁₁ is hydrogen.

6. The compound of claim 3, wherein R₁₀ and R₁₁ are both hydrogen.

7. The compound of claim 1, wherein Y and Z are absent, g and m are 1, and X is C═

O.

8. The compound of claim 1, wherein R₁-R₃ and R₅-R₇ are independently selected from halo and nitro.

9. A compound of selected from the group consisting of:

[4-(2-chloro-4-nitro-phenyl)-piperazin1-yl]-[3-(4-hydroxy-phenyl)-5-methylisoxazol-4-yl]-methanone;

[4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-phenyl-5-methyl-isoxazol-4-yl]-methanone;

[4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(4-amino-phenyl)-methylisoxazol-4-yl]-methanone;

[4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(4-azido-phenyl)-5-methylisoxazol-4-yl]-methanone;

[4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(2-chloro-phenyl)-5-methylisoxazol-4-yl]-methanone;

[4-(2-chloro-4-nitro-phenyl)-2-methyl-piperazin-1-yl]-[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanone;

[4-(2-chloro-4-nitro-phenyl)-2-methyl-piperazin-1-yl]-[3-phenyl-5-methylisoxazol-4-yl]-methanone;

[4-(4-nitro-pheny1)-piperazin-1-yl]-[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanone;

and [4-(4-nitro-pheny1)-piperazin-1-yl]-[3-(2,6-dichloro-phenyl)-5-methyl-isoxazol-4-yl]-methanone.

10. A compound of formula (III):

11. The compound of claim 10, wherein Ar¹ is substituted with hydrogen, hydroxyl, nitro, amino, or azide;

X is C═

O;

Y and Z are absent, and Ar³ is substituted with a halo group, a nitro group, or a combination of a halo and nitro group.

12. The compound of claim 10, wherein Q is carbon, T is oxygen, and R is nitrogen.

13. The compound of claim 10, wherein A and D are nitrogen.

14. The compound of claim 10, wherein R₄ and R₁₀ are independently hydrogen or methyl.

15. The compound of claim 10, wherein R₄ is methyl and R₁₀ is hydrogen.

16. The compound of claim 10, wherein A and D are both nitrogen.

17. The compound of claim 10, wherein R₁₀ is a methyl group and R₁₁ is hydrogen.

18. The compound of claim 10, wherein R₁₀ and R₁₁ are both hydrogen.

19. The compound of claim 10, wherein Y and Z are absent, g and m are 1, and X is C═

O.