Nucleoside phosphoramidate prodrugs

• US 8,580,765 B2
• Filed: 09/11/2012
• Issued: 11/12/2013
• Est. Priority Date: 03/30/2007
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Sofia, Michael Joseph, Du, Jinfa, Wang, Peiyuan, Nagarathnam, Dhanapalan
• Primary Examiner(s): Lewis, Patrick
• Application Number:
  US13/609,614
• Publication Number:
  US 20130029929A1
• Time in Patent Office: 427 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. A compound, or a stereoisomer thereof, represented by formula (I):

2. The compound according to claim 1, wherein:

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl; and

(c-i) R^3a is H and R^3b is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —

CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —

CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′

-OH)-Ph), CH₂SH, or lower cycloalkyl.

3. The compound according to claim 1, wherein:

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(c-i) R^3a is H and R^3b is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl; and

(e) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_3-qX_q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂.

4. The compound according to claim 1, wherein:

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c-i) R^3a is H and R^3b is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl; and

(e) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_3-qX_q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂.

5. The compound according to claim 1, wherein:

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c-i) R^3a is H and R^3b is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl; and

(e) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_3-qX_q, where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂.

6. A composition comprising the compound according to claim 1.

7. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable medium.

8. A composition comprising an effective amount of the compound according to claim 1 to treat a hepatitis C virus infection and a pharmaceutically acceptable medium.

9. A method of treating a subject infected by a virus selected from among hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, which comprises administering to the subject an effective amount of the compound according to claim 1.

10. The method of claim 9, wherein the virus is hepatitis C virus.

11. The method of claim 10, which further comprises administering to the subject an effective amount of another antiviral agent.

12. The method of claim 10, wherein the subject is a human.

13. A process for preparing the compound according to claim 1 comprising reacting a compound 4″

with a nucleoside analog 5′

;

14. The method of claim 11, wherein the subject is human.