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Publication Number
US-8765741-B2
Publication Date
2014-07-01
Expiration Date
Abstract
The invention is directed to 5,6-dihydro-1H-pyridin-2-one compounds of Formula I wherein X is CR3, andA is and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
Core Innovation
The disclosure defines compounds of Formula I with X as CR3 and Ring B as a 6-membered aryl optionally substituted by 1-3 R1 moieties, together with defined substituent variables R2, R3, Z, n, and R4-R16. The scope includes pharmaceutically acceptable salts, stereoisomers, hydrates, solvates, and prodrugs, and describes stereochemical descriptors such as exo/endo, syn/anti, and cis/trans relationships.
The document presents interconnected synthetic logic for preparing substituted benzo[1,2,4]thiadiazine/aza-tricyclic and methanesulfonamide-containing compounds, including related pyridine sulfonamide/sulfonyl intermediates. The examples describe formation of thiadiazinone acetic acid intermediates, substituted bicyclo[2.2.1]heptane derivatives, and further couplings to attach sulfonamide-containing heterocycles to bicyclic scaffolds, with characterization by NMR, LC-MS, and chiral HPLC for selected stereoisomers.
Multiple schemes describe the preparation of optically active and saturated or unsaturated cyclic beta-amino acid ester intermediates and related N-substituted derivatives. The disclosure further includes selected methanesulfonamide compounds with defined tricyclo[6.2.1.0(2,7)]undec-5-en or undec-5,9-dien frameworks, benzo[1,4]thiazin-7-yl motifs, and stereochemical or racemic variants, as well as listed dependent claim refinements that narrow specific substituent choices.
Claims Coverage
The provided claim set centers on one broad independent Formula I compound claim and a narrower independent claim to selected methanesulfonamide compounds, with dependent claims narrowing substituent choices and one claim reciting hepatitis C virus treatment. The inventive features below merge the repeated structural constraints and the explicit therapeutic-use feature.
Compound of Formula I with defined substituent scope
A compound of Formula I wherein X is CR3; A and Ring B are defined; Ring B is a 6-membered aryl optionally substituted by 1-3 R1 moieties; R1 includes H, halo, nitro, sulfonyl- and sulfonamide-related groups; and R2, R3, Z, n, R4-R16, R7, and R8 are constrained to specified allowable groups and optional substitution patterns, including pharmaceutically acceptable salts and stereoisomers.
Selected methanesulfonamide compounds with tricyclic motifs
A compound selected from specifically listed methanesulfonamide structures containing tricyclo[6.2.1.0(2,7)]undec-5-en or undec-5,9-dien frameworks and benzo[1,4]thiazin-7-yl or related heterocyclic motifs, including defined stereochemical or racemic variants, or a pharmaceutically acceptable salt thereof.
Narrowed substituent and parameter limitations
Dependent claim refinements restrict R3 to hydrogen or C1-C6 alkyl, fix n at 1, and restrict R9-R16 to H or hydroxy.
Treatment of hepatitis C virus infection
A method for treating hepatitis C virus infection in a mammal by administering a therapeutically effective amount of the claimed compound or a pharmaceutically acceptable salt thereof.
The claim coverage is dominated by a broad Formula I chemical class with tightly constrained substituent variables, a narrower claim to selected methanesulfonamide tricyclic compounds, dependent limitations on specific substituents and n, and an explicit therapeutic-use claim for hepatitis C virus infection.
Stated Advantages
Treating or preventing hepatitis C virus infection.
Providing compounds that can act as NS5B polymerase inhibitors.
Allows use with additional antiviral agents or immunomodulatory agents, and administration with pharmaceutically acceptable excipients.
Documented Applications
Treating hepatitis C virus infection in a mammal by administering a therapeutically effective amount of the claimed compounds or a pharmaceutically acceptable salt thereof.
Preventing hepatitis C virus infection by administering prophylactically effective amounts of the claimed compounds or a pharmaceutically acceptable salt thereof.
Hepatitis C virus evaluation through NS5B polymerase inhibition and HCV replicon activity testing.
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