Hepatitis b core protein modulators
Inventors
Turner, Jr., William W. • Arnold, Lee D. • Maag, Hans • Li, Leping • Bures, Mark G. • Haydar, Simon Nicolas • Francis, Samson
Assignees
Indiana University Research and Technology Corp • Assembly Biosciences Inc
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Publication Number
US-11814376-B2
Publication Date
2023-11-14
Expiration Date
Abstract
The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.
Core Innovation
The disclosure relates to compound 1553, HBV core protein allosteric modifiers (CpAM), and pharmaceutically acceptable salts thereof for hepatitis B treatment. These compounds have allosteric effector properties directed to the HBV core protein, including disruption of HBV core protein multimerization and/or capsid assembly.
The document also describes substituted thiazepine-8-carboxamide derivatives and related target compounds, including compound 11066, compound 11063-A, compound 11063-B, compound 761, compound 762, compound 11032, compound 11033, and alkenyl/alkynyl-amino sidechain analogs. The synthesis focuses on constructing and modifying sidechains attached to a thiazepine-8-carboxamide scaffold, and includes protection/deprotection, sulfonylation using mesylate formation, ether formation, nucleophilic substitution, Bpin formation followed by Suzuki-type coupling, oxidation of thio-alcohol to sulfonyl, conversion to mesylates and azides, reductions, and derivatization to amines or amine salts.
The disclosure further provides broad chemical Markush definitions, example disclosed compound structures, stereoisomers, pharmaceutically acceptable salts, N-oxides, and analytical characterization using TLC, LC-MS, HPLC, and 1H NMR for intermediates and final products. It also includes a method-of-use statement for treating hepatitis B by administering compound 1553, or a pharmaceutically acceptable salt, in combination with one or more additional active compounds.
Claims Coverage
The independent claim coverage centers on a method for treating hepatitis B infection by administering compound 1553, or a pharmaceutically acceptable salt, together with one or more additional active compounds, or pharmaceutically acceptable salts. The dependent claims further define the additional active compounds by specific HBV-directed classes and by nucleoside analogs that interfere with viral polymerase, and one dependent claim requires at least two additional active compounds.
Combination therapy with compound 1553 and additional active compounds for HBV
A method for treating a hepatitis B infection in a patient in need thereof, comprising administering compound 1553 or a pharmaceutically acceptable salt thereof and one or more additional active compounds or pharmaceutically acceptable salts thereof.
HBV capsid assembly promoter as the additional active compound
The one or more additional active compounds is an HBV capsid assembly promoter.
Selected HBV-directed agent classes for the additional active compounds
The one or more additional active compounds are selected from HBV capsid assembly promoters, viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, nucleocapsid formation disruptors, cccDNA formation inhibitors, antiviral core protein mutants, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
Nucleoside analogs interfering with viral polymerase
The one or more additional active compounds includes one or more nucleoside analog additional active compounds that interfere with viral polymerase, selected from entecavir, lamivudine, telbivudine, adefovir dipivoxil, tenofovir, prodrugs of tenofovir, clevudine, and besifovir.
Entecavir as the additional active compound
The one or more additional active compound(s) is entecavir.
At least two additional active compounds
The method further comprises administration of compound 1553 and at least two additional active compounds or a pharmaceutically acceptable salt thereof.
The claim set is directed to treating hepatitis B infection using compound 1553 in combination with one or more additional active compounds or salts. Dependent claims specify HBV capsid assembly promoters, an enumerated HBV-directed agent group, nucleoside analogs that interfere with viral polymerase including entecavir, and an embodiment requiring at least two additional active compounds alongside compound 1553.
Stated Advantages
Disrupts HBV core protein multimerization and/or capsid assembly, and is positioned to affect upstream viral assembly steps and upstream cccDNA transcription processes.
Documented Applications
Treating a hepatitis B infection in a patient in need thereof by administering compound 1553 or a pharmaceutically acceptable salt in combination with one or more additional active compounds or salts.
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