Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections

• US 9,403,863 B2
• Filed: 09/11/2012
• Issued: 08/02/2016
• Est. Priority Date: 09/12/2011
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Inventors: Surleraux, Dominique, Dousson, Cyril B., Gosselin, Gilles, Dukhan, David, Pierra, Claire, Peyronnet, Jerome
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US13/610,722
• Publication Number:
  US 20130064794A1
• Time in Patent Office: 1,421 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disorders, 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. In certain embodiments, provided herein are compounds according to Formula I:

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

Claims

1. A compound of Formula II:

2. The compound of claim 1, wherein Z is hydroxyl.

3. The compound of claim 1, wherein U is hydrogen or methyl.

4. The compound of claim 1, wherein W is C₁-C₆ unsubstituted alkyl or C₁-C₆ alkyl substituted with fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, or cyano.

5. The compound of claim 1, wherein X is O.

6. The compound of claim 1, wherein Y is hydrogen or hydroxyl.

7. The compound of claim 1, wherein Base is 9-adeninyl, 1-cytosinyl, 9-guaninyl, 1-thyminyl, or 1-uracilyl.

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

9. The pharmaceutical composition of claim 8, wherein the composition is an oral formulation.

10. 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 or composition of any one of claims 1-9.

11. The method of claim 10, wherein the host is a human.

12. The compound of claim 1, wherein Q is —

O—

or —

S—

; and

R^γ

is alkyl.

13. The compound of claim 1, wherein

acyl at each occurrence is selected from the group consisting of acetyl, trifluoroacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α

-methoxy-α

-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 2-(4-chlorophenyl)acetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl,2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7 chlorododecafluoro-heptanoyl, nona-fluoro-3,6-dioxa-heptanoyl, methoxybenzoyl, methyl 3 -amino-5-phenylthiophene-2-carbonyl, 3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl -propionyl, benzoyl, O-acetylmandeloyl, pivaloyl 1-adamantane-carbonyl, cyclohexane-carbonyl, cyclopropane-carbonyl, cyclobutane-carbonyl, perfluorocyclohexyl carbonyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenoyl, isovaleroyl, 1-pyrrolidinecarbonyl, and 4-phenylbenzoyl;

aryl at each occurrence is independently unsubstituted phenyl, biphenyl, or naphthyl; and

heterocyclyl at each occurrence is independently a C₃ to C₂₀ monovalent monocyclic non-aromatic ring system or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are O S, or N;

the heterocyclyl is bonded to the rest of the molecule through the non-aromatic ring; and

where the heterocyclyl is unsubstituted.

14. A compound selected from