Compounds and pharmaceutical compositions for the treatment of viral infections

Patent metadata

Field	Value
Publication number	US-9249173-B2
Application number	US-201414197078-A
Country	US
Kind code	B2
Filing date	Mar 4, 2014
Priority date	Dec 28, 2006
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disorder, including HCV and/or HBV infections. Specifically, compound and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

First claim

What is claimed is:

1. A method for the treatment of a host infected with a Flaviviridae virus or hepatitis B virus, comprising administering an effective treatment amount of a compound of formula:

or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof, wherein:
R y is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, amino, heterocyclyl or heteroaryl;
R a and R b are selected as follows:
i) R a and R b are each independently hydrogen or optionally substituted alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl; or
ii) R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and

R 1 is ribavirin, viramidine, valopicitabine, 2′-β-methyl-cytidine, 2′-β-methyl-guanosine, 2′-β-methyl-uridine, 2′-β-methyl-thymidine, 2′-β-methyl-adenosine, 2′-β-methyl-inosine, L-ddA, PSI-6130, MK-0608, resiquimod, celgosivir, lamivudine, entecavir, telbivudine, racivir, emtricitabine, clevudine, amdoxovir, or valtorcitabine.

2. The method of claim 1 , wherein the virus is hepatitis C.

3. The method of claim 2 , wherein the host is a human.

4. The method of claim 2 wherein the compound is

or a pharmaceutically acceptable salt thereof.

5. The method of claim 2 , wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt thereof to the liver of said host.

6. The method of claim 2 , wherein said compound or pharmaceutically acceptable salt thereof is administered in combination or alternation with an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme.

7. The method of claim 5 , wherein said compound or pharmaceutically acceptable salt thereof is administered in combination or alternation with an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme.

8. The method of claim 7 , wherein the interferon is pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta or interferon γ-1b.

9. The method of claim 5 , wherein the host is a human.

10. The method of claim 9 , wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt thereof to the liver of said host.

11. The method of claim 1 , comprising treating a human host infected with hepatitis B virus.

12. A method for the treatment of a host infected with a Flaviviridae virus or hepatitis B virus, comprising administering an effective treatment amount of a compound of formula:

wherein R y is hydroxyalkyl or —C(CH 3 ) 2 CH 2 OH; and
R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl;
and wherein optionally said compound or pharmaceutically acceptable salt thereof is administered in combination or alternation with interferon alfa-2b, Peginterferon alfa-2a, lamivudine, entecavir, telbivudine, racivir, emtricitabine, clevudine, amdoxovir, valtorcitabine, tenofovir or adefovir.

13. The method of claim 12 , wherein said administration directs a substantial amount of said compound or pharmaceutically acceptable salt thereof to the liver of said host.

14. The method of claim 1 , wherein the compound is administered in combination or alternation with ribavirin.

15. The method of claim 14 , wherein the compound has the formula:

or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof.

16. The method of claim 14 , wherein the compound has the formula:

or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof.

17. The method of claim 14 , wherein the compound has the formula:

or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof.

18. The method of claim 1 , wherein the compound has the formula:

wherein R 2 and R 3 are each independently H, or R 2 and R 3 are linked to form a cyclic group by an alkyl, ester or carbamate linkage;

or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof.

19. The method of claim 14 having the formula:

wherein
each R L is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester, a lipid, an amino acid; an amino acid residue; or a carbohydrate;

or a pharmaceutically acceptable salt, a tautomeric or polymorphic form thereof.

20. The method of claim 1 , wherein the compound is selected from:

21. The method of claim 20 , wherein the virus is hepatitis C.

22. The method of claim 21 , wherein the host is a human.

23. The method of claim 12 , wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Idenix Pharmaceuticals Inc
• Centre Nat Rech Scient
• Univ Montpellier Ii
• Idenix Pharmaceuticals Llc

Inventors

• Sommadossi Jean-Pierre
• Gosselin Gilles
• Pierra Claire
• Perigaud Christian
• Peyrottes Suzanne

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title