Enhanced anti-influenza agents conjugated with anti-inflammatory activity

• US 10,130,714 B2
• Filed: 03/15/2013
• Issued: 11/20/2018
• Est. Priority Date: 04/14/2012
• Status: Active Grant

• Current Assignee: Academia Sinica (Government of The Republic of China)
• Original Assignee: Academia Sinica (Government of The Republic of China)
• Inventors: Wong, Chi-Huey, Fang, Jim-Min, Liu, Kung-Cheng, Jan, Jia-Tsrong, Cheng, Yih-Shyun E., Cheng, Ting-Jen R.
• Primary Examiner(s): McMillian, Kara R
• Application Number:
  US13/836,356
• Publication Number:
  US 20130274229A1
• Time in Patent Office: 2,076 Days
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 309/28 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

Novel dual-targeted, bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents are disclosed. Exemplary drugs according to the invention include caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1), ZA-7-CA-amide (7) and ZA-7-Nap (43) for simultaneous inhibition of influenza virus neuraminidase and suppression of proinflammatory cytokines. Synthetic methods for preparation of these enhanced anti-influenza conjugate drugs are provided. The synthetic bifunctional ZA conjugates act synergistically towards protection of mice lethally infected by H1N1 or H5N1 influenza viruses. The efficacy of ZA-7-CA, ZA-7-CA-amide and ZA-7-Nap conjugates is much greater than the combination therapy of ZA with anti-inflammatory agents.

Claims

1. A dual anti-influenza and anti-inflammatory compound selected from the group consisting of:

2. A dual-active pharmaceutical composition for simultaneously inhibiting influenza virus and inflammation, the composition comprising:

a compound of claim 1,

or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 2, wherein the compound inhibits both human and avian influenza virus.

4. The pharmaceutical composition of claim 2, wherein the compound inhibits at least one of H1N1 and H5N1 strains of influenza virus.

5. A method for treating influenza infection in a subject, the method comprising:

administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 2.

6. The method of claim 5, wherein the subject has, is suspected of having, or is at risk for influenza virus infection.