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Publication Number
US-9751857-B2
Publication Date
2017-09-05
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 (III) or a pharmaceutically acceptable salt thereof. The compounds are characterized by a defined substitution pattern in which the substituents C(=O)N(R6)2 and C(=O)NR4 are in a 1,3-position with respect to each other, ring B is a monocyclic aryl ring, and R4 is H. The R6 groups attached to the same N atom are taken together with the N atom to form an optionally substituted C2-C10 heterocycloalkyl ring, optionally comprising a moiety selected from N-R4 and optionally substituted with 0-5 substituents selected from R2.
R2 and R5 are independently selected from halo, CN, NO2, -(L)m-OR8, -(L)m-C(=O)R9, -(L)m-OC(=O)R9, -(L)m-CO2R8, -(L)m-CH(R8)2, -(L)m-N(R8)2, -(L)m-C(OH)(R8)2, -(L)m-C(NH2)(R8)2, C1-C6 alkyl, and C1-C6 heteroalkyl. Each RB is independently H or C1-C6 alkyl, R9 is C1-C6 alkyl or C3-C10 cycloalkyl, each occurrence of y is independently selected from 0, 1, 2, 3 and 4, each occurrence of x is 0, L is independently a bivalent radical selected from -(C1-C3 alkylene)m- and -(C1-C3 alkylene)m-O-(C1-C3 alkylene)m-, and each occurrence of m is independently 0, 1 or 2.
The provided material also shows example compounds within the Formula (III) scaffold, including sulfonamide-containing structures with halogenated aryl substituents and substituted heterocycloalkyl motifs, together with reported 1H NMR spectral data for specific embodiments. The disclosure further ties the compound class to HBV-related therapeutic claims.
Claims Coverage
The provided claim coverage centers on one independent Formula (III) compound claim with detailed structural constraints, and dependent claims directed to HBV treatment, co-administration, comparative viral load reduction, lower dose or frequency for additional therapeutic agents, refractory-individual eligibility, and TLR-agonist selection.
Formula (III) compound with 1,3-positioned carbonyl substituents
A compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein the substituents C(=O)N(R6)2 and C(=O)NR4 are in a 1,3-position with respect to each other and ring B is a monocyclic aryl ring.
R6-derived heterocycloalkyl ring with fixed R4
R4 is H, and the R6 groups attached to the same N atom are taken together with the N atom to form an optionally substituted C2-C10 heterocycloalkyl ring, optionally comprising N-R4 and optionally substituted with 0-5 substituents selected from R2.
Defined R2, R5, RB, R9, x, y, L, and m constraints
R2 and R5 are independently selected from the stated substituent set; each RB is independently H or C1-C6 alkyl; R9 is C1-C6 alkyl or C3-C10 cycloalkyl; each y is independently 0, 1, 2, 3 or 4; each x is 0; L is independently a bivalent radical selected from -(C1-C3 alkylene)m- and -(C1-C3 alkylene)m-O-(C1-C3 alkylene)m-; and each m is independently 0, 1 or 2.
HBV treatment by administering a therapeutically effective amount
A method of treating HBV infection in an individual by administering a therapeutically effective amount of a Formula (III) compound.
Co-administration with at least one additional therapeutic agent
The method further includes co-administering the Formula (III) compound together with at least one additional therapeutic agent.
Lower dose or lower frequency for an additional therapeutic agent
The method includes administering the Formula (III) compound such that at least one additional therapeutic agent can be administered at a lower dose or frequency than when the additional therapeutic agent is given alone to treat HBV infection.
Greater viral load reduction than specified comparators
Administering the compound reduces viral load in an individual to a greater extent than administering a compound selected from the specified HBV comparator group, including combinations thereof.
Refractory-individual eligibility precondition
Prior to administering a therapeutically effective amount of the Formula (III) compound, the individual is known to be refractory to one or more specified HBV-related compounds or inhibitors.
TLR-agonist selection as an additional therapeutic component
Selecting a TLR-agonist from 9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine or methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate.
Overall, the claim coverage is directed to a tightly defined Formula (III) compound class with fixed positional and variable-substituent constraints, and extends to HBV treatment methods with co-administration, comparative efficacy, dosing/frequency, refractory-individual, and TLR-agonist features.
Stated Advantages
Reduces viral load in an individual to a greater extent than administering specified comparator agents.
Allows at least one additional therapeutic agent to be administered at a lower dose or frequency than when the additional therapeutic agent is given alone.
Documented Applications
Treating HBV infection in an individual by administering a therapeutically effective amount of a Formula (III) compound.
HBV treatment with co-administration of at least one additional therapeutic agent.
HBV treatment in individuals known to be refractory to one or more specified HBV-related compounds or inhibitors.
HBV treatment using a TLR-agonist selected from the specified options as an additional therapeutic component.
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