3′,5′-cyclic phosphoramidate prodrugs for HCV infection

• US 9,109,001 B2
• Filed: 05/21/2013
• Issued: 08/18/2015
• Est. Priority Date: 05/22/2012
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Parsy, Christophe Claude, Alexandre, Francois-Rene, Dousson, Cyril B., Dukhan, David, Pierra, Claire, Mayes, Benjamin Alexander, Moussa, Adel M., Surleraux, Dominique, Stewart, Alistair James
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US13/899,257
• Publication Number:
  US 20130315866A1
• Time in Patent Office: 819 Days
• Field of Search: 536/26.12, 514/48
• US Class Current: 1/1
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

Claims

1. A compound of Formula I:

2. The compound of claim 1 wherein:

Z is -LC(O)O(L)_pCR₃, -LOC(O)(L)_pCR₃, or -LC(O)O(L)_pCy;

each L is independently alkylene or substituted alkylene;

Cy is unsubstituted cycloalkyl; and

p is 0 or 1.

3. The compound of claim 2, wherein each L is independently C₁-C₁₀ alkylene or C₁-C₁₀ substituted alkylene.

4. The compound of claim 2, wherein Cy is C₃-C₁₀ unsubstituted cycloalkyl.

5. The compound of claim 1 wherein X is unsubstituted C₁-C₁₀ alkoxyl.

6. The compound of claim 1 wherein X is hydroxyl.

7. The compound of claim 1 wherein Y is fluoro.

8. The compound of claim 1 wherein Y is acetoxyl.

9. The compound claim 1 wherein Y is hydroxyl.

10. The compound of claim 1 according to any of formulas II, III, or IV:

11. The compound of claim 1 according to formula Ia or Ib:

12. The compound of claim 1 wherein:

Z is -L-S—

S-(L)_pCR₃,or -LSC(O)(L)_pCR₃;

each L is independently alkylene or substituted alkylene;

p is 0 or 1.

13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

14. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound of claim 1.

15. The method of claim 14, wherein the compound is administered in combination or alternation with a second anti-viral agent, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof

16. The compound of claim 1, wherein:

X is hydrogen, hydroxyl, or —

OR′

wherein R′

is C₁ to C₁₀ unsubstituted alkyl;

Y is hydroxyl, acetoxyl, or fluoro;

Z is C₁ to C₁₀ alkyl substituted with;

fluoro, chloro, bromo, iodo, hydroxyl, —

NH₂, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—

NH₂ substituted with one or two C₁ to C₁₀ unsubstituted alkyl;

or

—

NH₂ substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl; and

R is hydrogen, unsubstituted C₁ to C₁₀ alkyl, unsubstituted C₃ to C₁₅ cycloalkyl, unsubstituted phenyl, unsubstituted biphenyl, unsubstituted naphthyl, heteroaryl having from five to twenty ring atoms, or C₁ to C₁₀ alkyl substituted with;

fluoro, chloro, bromo, iodo, hydroxyl, —

NH₂, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—

NH₂ substituted with one or two unsubstituted C₁ to C₁₀ alkyl;

or

—

NH₂ substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl.

17. The compound of claim 10, wherein:

Y is hydroxyl, acetoxyl, or fluoro;

Z is C₁ to C₁₀ alkyl substituted with;

fluoro, chloro, bromo, iodo, hydroxyl, —

NH₂, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—

NH₂ substituted with one or two unsubstituted C₁ to C₁₀ alkyl;

or

—

NH₂ substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl; and

R is hydrogen, unsubstituted C₁ to C₁₀ alkyl, unsubstituted C₃ to C₁₅ cycloalkyl, unsubstituted phenyl, unsubstituted biphenyl, unsubstituted naphthyl, heteroaryl having from five to twenty ring atoms, or C₁ to C₁₀ alkyl substituted with;

fluoro, chloro, bromo, iodo, hydroxyl, —

NH₂, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—

NH₂ substituted with one or two unsubstituted C₁ to C₁₀ alkyl;

or

—

NH₂ substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl.

18. The compound of claim 11, wherein:

X is hydrogen, hydroxyl, or —

OR′

wherein R′

is unsubstituted C₁ to C₁₀ alkyl;

Y is hydroxyl, acetoxyl, or fluoro;

Z is C₁ to C₁₀ alkyl substituted with;

fluoro, chloro, bromo, iodo, hydroxyl, —

NH₂, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—

NH₂ substituted with one or two unsubstituted C₁ to C₁₀ alkyl;

or

—

NH₂ substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl; and

R is hydrogen, unsubstituted C₁ to alkyl, unsubstituted C₃ to C₁₅ cycloalkyl, unsubstituted phenyl, unsubstituted biphenyl, unsubstituted naphthyl, heteroaryl having from five to twenty ring atoms, or C₁ to C₁₀ alkyl substituted with;

fluoro, chloro, bromo, iodo, hydroxyl, —

NH₂, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate;

—

NH₂ substituted with one or two unsubstituted C₁ to C₁₀ alkyl;

or

—

NH₂ substituted with one or two unsubstituted phenyl, unsubstituted biphenyl, or unsubstituted naphthyl.

19. The compound of claim 10, wherein:

R is H, and Z and Y are selected from one of the following combinations;

Z=(S)-iPrOC(O)CH(CH₃)— and

Y=F;

Z=(S)-iPrC(O)OCH₂CH(CH₃)— and

Y=F;

Z=(S)-iBuOC(O)CH(CH₃)— and

Y=F;

Z=(S)-iPrOC(O)CH(CH₃)— and

Y=OH;

Z=EtOC(O)C(CH₃)₂— and

Y=F;

Z=(S)-iPrC(O)OCH₂CH(Et)— and

Y=F;

Z=EtC(O)O(CH₂)₂— and

Y=F;

Z=(S)-cPnOC(O)CH(CH₃)— and

Y=F;

Z=iPrOCO(CH₂)₂— and

Y=F; and

Z=tBuC(O)S(CH₂)₂— and

Y=F.

20. The compound of claim 19, according to the formula:

21. The compound according to claim 2 selected from

22. The compound according to claim 12 selected from

23. The compound of claim 1 according to formula (VII):

24. The compound of claim 1 according to formula (VIII):

25. A compound according to Formula V

26. The compound of claim 25 where ring A is oxacyclopropyl or oxacyclobutyl.

27. A compound of Formula VI is provided:

28. The compound of claim 27 where R^B and R^C are methyl;

or R^B is hydrogen and R^C is methyl.