Hepatitis B core protein allosteric modulators
Inventors
Turner, Jr., William W. • Arnold, Lee Daniel • Maag, Hans • Zlotnick, Adam
Assignees
Indiana University Research and Technology Corp • Assembly Biosciences Inc
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Publication Number
US-10947224-B2
Publication Date
2021-03-16
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 invention relates to compounds of Formula 1 and their use in a method of treating a hepatitis B infection in a patient in need thereof by administering an effective amount of a compound of Formula 1. Formula 1 defines multiple variable moieties, including T, Y, RY, L, R2, and additional independently selected moieties R4 to R10, and includes pharmaceutically acceptable salts. The compound framework uses selected structural options for aromatic, heteroaryl, cycloalkyl, and heterocycloalkyl groups, together with defined linker and substituent patterns.
In the described scope, T is selected from C(O), CH2C(O), N(C(O)CH3), NH, O, and S(O)z, with z being 0, 1 or 2. Y is NRY, and RY is selected from H, methyl, ethyl, propyl, phenyl, and benzyl. L is defined as a bond or C1-4 straight chain alkylene optionally substituted by one or two substituents and optionally interrupted by O, while R2 is selected from phenyl or naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl options with optional substitution patterns.
The disclosure also includes characterizations of substituted Formula 1-type compounds and related dibenzo[b,f][1,4]thiazepine, sulfonamide, sulfone, amide, ester, and acid derivatives, with analytical data such as molecular ion mass values, 1H NMR spectra in DMSO-d6, LC-MS, and chiral chromatography. The chemistry portion describes synthesis of intermediates and final compounds associated with the Formula 1 compound class, including intermediate acids, thioaryl nitrile/benzoate intermediates, and enantiopure compounds obtained by racemate resolution.
Claims Coverage
The consolidated claim coverage includes one independent claim directed to a hepatitis B treatment method by administering an effective amount of a Formula 1 compound, with pharmaceutically acceptable salts included. Across the provided claim text, the inventive features center on the structural definition of Formula 1 through T, Y/RY, L, R2, and additional moieties, with dependent refinements narrowing L and R2.
Hepatitis B treatment via Formula 1 compound administration
A method of treating a hepatitis B infection in a patient in need thereof by administering an effective amount of a compound of Formula 1, including pharmaceutically acceptable salts.
Formula 1 substituent-variable framework
Formula 1 is defined by T selected from C(O), CH2C(O), N(C(O)CH3), NH, O, and S(O)z; Y defined as NRY; RY selected from H, methyl, ethyl, propyl, phenyl, and benzyl; L defined as a bond or C1-4 straight chain alkylene optionally substituted and optionally interrupted by O; R2 selected from phenyl or naphthyl, heteroaryl, cycloalkyl, and heterocycloalkyl options; and additional moieties R4 to R10.
Dependent narrowing of linker L
Dependent claims refine L by specifying CH2 or C2-3 alkylene-O, and by further defining L as a bond or substituted C1-4 straight chain alkylene.
Dependent narrowing of R2 substitution patterns
Dependent claims refine R2 by specifying phenyl substituted by one or two substituents, 4-6 membered heterocycloalkyl or C4-6 cycloalkyl, and specific cyclic substituents including tetrahydropyranyl, tetrahydrofuranyl, cyclopentyl, cyclohexyl, and cyclobutyl.
Coverage centers on a hepatitis B treatment method achieved by administering an effective amount of a Formula 1 compound. The core inventive structure is controlled by the defined selections for T, Y/RY, L, R2, and additional moieties, with dependent claims narrowing the linker and ring substituent scope.
Stated Advantages
Allosteric modulation of HBV capsid core protein behavior is described as favoring assembly-active or misassembled capsids.
The disclosed CpAMs are described as perturbing upstream steps including cccDNA transcription, RNA stability, and protein-protein interactions.
Combination therapy with other HBV antivirals is described as an option to address limitations of nucleos(t)ide analogs and interferon α.
Documented Applications
Treating a hepatitis B infection in a patient in need thereof by administering an effective amount of a Formula 1 compound, including pharmaceutically acceptable salts.
Combination therapy with other HBV antivirals for hepatitis B infection.
Synthetic schemes and analytical work for multiple intermediates and final compounds derived from a thiazepine core, including chiral separation yielding enantiopure compounds.
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