SYNTHESIS OF OSELTAMIVIR CONTAINING PHOSPHONATE CONGENERS WITH ANTI-INFLUENZA ACTIVITY

• US 20100113397A1
• Filed: 08/29/2008
• Published: 05/06/2010
• Est. Priority Date: 08/31/2007
• Status: Active Grant

• Current Assignee: Academia Sinica (Government of The Republic of China)
• Original Assignee: Academia Sinica (Government of The Republic of China)
• Inventors: Fang, Jim-Min, Shie, Jiun-Jie, Cheng, Yih-Shyun Edmond, Jan, Jia-Tsrong, Wong, Chi-Huey
• Granted Patent: US 7,888,337 B2
• Time in Patent Office: Days
• US Class Current: 514/119
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• 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

Abstract

Novel phosphonate compounds are described. The compounds have activity as neuraminidase inhibitors against wild-type and H274Y mutant of H1N1 and H5N1 viruses. The present disclosure also provides an enantioselective synthetic route to known neuraminidase inhibitors oseltamivir and the anti-flu drug Tamiflu®, as well as novel phosphonate compounds, via D-xylose. Another efficient and flexible synthesis of Tamiflu and the highly potent neuraminidase inhibitor Tamiphosphor was also achieved in 11 steps and >20% overall yields from the readily available fermentation product (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol. Most of the reaction intermediates were obtained as crystals without tedious purification procedures. The key transformations include an initial regio- and stereoselective bromoamidation of a bromoarene cis-dihydrodiol, as well as the final palladium-catalyzed carbonylation and phosphonylation.

Claims

1. A composition comprising:

a therapeutically effective amount of formula I;

2. The composition of claim 1, wherein Formula I is:

3. The composition of claim 1, wherein Formula I is:

4. The composition of claim 1, wherein Formula I is:

5. The composition of claim 1, wherein Formula I is:

6. The composition of claim 1, wherein Formula I is:

7. The composition of claim 1, wherein Formula I is:

8. The composition of claim 1, wherein Formula I is:

21. The composition of claim 1, wherein Formula I is:

9. A composition comprising:

a therapeutically effective amount of at least one of;

10. A method comprising:

making a composition of formula I;

11. A product by the process of claim 10.

12. A method comprising:

providing a therapeutically effective amount of a composition having Formula I;

13. The method of claim 12, wherein the organism is an animal.

14. The method of claim 13, wherein the organism is a human.

15. The method of claim 12, wherein the organism is exhibiting influenza-like symptoms.

16. The method of claim 12, wherein Formula I is:

17. The method of claim 12, wherein Formula I is:

18. The method of claim 12, wherein Formula I is:

19. The method of claim 12, wherein Formula I is:

20. The method of claim 12, wherein Formula I is:

22. The method of claim 12, wherein Formula I is:

23. A method comprising:

providing a composition having therapeutically effective amount of at least one of;

24. The method of claim 23, wherein the organism is an animal.

25. The method of claim 24, wherein the organism is a human.

26. The method of claim 23, wherein the organism is exhibiting influenza-like symptoms.