Pyridyl reverse sulfonamides for HBV treatment
Inventors
Clark, Ryan C. • Truong, Yen • Stock, Nicholas • Jacintho, Jason
Assignees
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Publication Number
US-9765050-B2
Publication Date
2017-09-19
Expiration Date
Abstract
The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
Core Innovation
The invention relates to a compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof. In Formula Ia, R1 and R3 are each halo, and R4 is selected from C1-6-alkyl, C3-7-cycloalkyl, (C1-6-alkyl)-(C3-7-cycloalkyl), and (C1-6-alkyl)-aryl, wherein the C3-7-cycloalkyl and (C1-6-alkyl)-aryl groups are optionally substituted with C1-6-alkyl.
The invention further relates to pyridyl reverse sulfonamide compounds for the treatment and/or prophylaxis of hepatitis B virus (HBV). The compounds can be used in monotherapy or in combination therapy, and the therapeutic use covers treating HBV infection and prophylaxis for latent infection, including reducing viral load and preventing recurrence.
The proposed antiviral mechanism is described in terms of disruption and/or attenuation of HBV viral replication steps, including virion assembly/disassembly, virion maturation, virus egress, and possible effects related to HBV cccDNA formation and activity. The document also refers to compound embodiments and characterized analogs, together with HBV replication inhibition data using dot-blot and real-time PCR/qPCR formats.
Claims Coverage
The claim coverage centers on 2 independent themes: a Formula Ia compound with constrained substituents, and HBV therapeutic use of the compound. The claim set also includes pharmaceutical composition coverage and combination-treatment refinements with additional therapeutic agents.
Formula Ia compound with halo R1 and R3 and selected R4
A compound of Formula Ia, or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein R1 is halo, R3 is halo, and R4 is selected from C1-6-alkyl, C3-7-cycloalkyl, (C1-6-alkyl)-(C3-7-cycloalkyl), and (C1-6-alkyl)-aryl, with optional C1-6-alkyl substitution on the cycloalkyl and aryl groups.
Pharmaceutical composition including the Formula Ia compound
A pharmaceutical composition comprising a compound according to Formula Ia, or a pharmaceutically acceptable salt, solvate, or N-oxide form, together with at least one pharmaceutically acceptable carrier.
Treating HBV infection by administering the Formula Ia compound
A method of treating an HBV infection by administering to an individual having an HBV infection a therapeutically effective amount of the compound according to Formula Ia.
HBV treatment with additional therapeutic agents
A method further administering an individual with at least one additional therapeutic agent selected from specified HBV-related drugs, vaccines, and inhibitors, or combinations thereof, including pegylated interferon alpha, pegylated interferon lambda, pegylated interferon gamma, SM360320, and AZD 8848.
Overall, the claim coverage is anchored by the structural definition of Formula Ia with halo substituents at R1 and R3 and a defined R4 selection, and extends to pharmaceutical compositions and HBV treatment methods, including co-therapy options with enumerated additional therapeutic agents.
Stated Advantages
Treating HBV infection.
Prophylaxis for latent infection.
Reducing viral load.
Preventing recurrence.
Reducing adverse physiological impact.
Inducing remission and hepatic injury recovery.
Mitigating long-term antiviral therapy impact.
Disrupting and/or attenuating HBV viral replication steps, including virion assembly/disassembly, virion maturation, virus egress, and possible effects related to HBV cccDNA formation and activity.
Documented Applications
Therapeutic treatment of HBV infection by administering a therapeutically effective amount of the claimed compound.
Prophylaxis for latent HBV infection.
Treatment regimens using monotherapy or combination therapy, including co-therapy with HBV polymerase inhibitors, immunomodulatory agents, interferons, viral entry/maturation inhibitors, capsid assembly modulators, reverse transcriptase inhibitors, cyclophilin/TNF inhibitors, TLR agonists, HBV vaccines, pegylated interferon alpha, pegylated interferon lambda, pegylated interferon gamma, SM360320, and AZD 8848.
HBV replication inhibition in assays referenced as dot-blot and real-time PCR/qPCR formats, with EC50 and CC50 determination.
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