Nucleoside phosphoramidate prodrugs

• US 7,964,580 B2
• Filed: 03/21/2008
• Issued: 06/21/2011
• Est. Priority Date: 03/30/2007
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Sofia, Michael Joseph, Du, Jinfa, Wang, Peiyuan
• Primary Examiner(s): Lewis; Patrick T
• Application Number:
  US12/053,015
• Publication Number:
  US 20100016251A1
• Time in Patent Office: 1,187 Days
• Field of Search: None
• US Class Current: 514/51
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/073 with 2-deoxyribosyl as the saccharide radical
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure:

Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.

Claims

1. (S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester or a stereoisomer thereof.

2. A composition comprising the compound or a stereoisomer thereof as claimed in claim 1 and a pharmaceutically acceptable medium.

3. A composition for treating a hepatitis C virus, which comprises an effective amount of the compound or a stereoisomer thereof as claimed in claim 1 and a pharmaceutically acceptable medium.

4. A method of treating a subject infected by a virus, which comprises:

administering to the subject an effective amount of the compound or a stereoisomer thereof as claimed in claim 1;

wherein the virus is selected from among hepatitis C virus, West Nile virus, a yellow fever virus, a dengue virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, and a Japanese encephalitis virus.

5. A method of treating a hepatitis C virus infection in a subject in need thereof, which comprises:

administering to the subject an effective amount of the compound or a stereoisomer thereof as claimed in claim 1.

6. A process for preparing the compound or a stereoisomer thereof as claimed in claim 1, said process comprising:

reacting a compound 4″

with a nucleoside analog 5′

7. A product comprising the compound or a stereoisomer thereof as claimed in claim 1 obtained by a process comprising:

reacting a compound 4″

with a nucleoside analog 5′

8. (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.

9. A composition comprising the compound as claimed in claim 8 and a pharmaceutically acceptable medium.

10. A composition for treating a hepatitis C virus, which comprises an effective amount of the compound as claimed in claim 8 and a pharmaceutically acceptable medium.

11. A method of treating a subject infected by a virus, which comprises:

administering to the subject an effective amount of the compound as claimed in claim 8;

wherein the virus is selected from among hepatitis C virus, West Nile virus, a yellow fever virus, a dengue virus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrhea virus, and a Japanese encephalitis virus.

12. A method of treating a hepatitis C virus infection in a subject in need thereof, which comprises:

administering to the subject an effective amount of the compound as claimed in claim 8.

13. A process for preparing the compound as claimed in claim 8, said process comprising:

reacting a compound 4″

with a nucleoside analog 5′

14. A product comprising the compound as claimed in claim 8 obtained by a process comprising:

reacting a compound 4″

with a nucleoside analog 5′