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Publication Number
US-11692005-B2
Publication Date
2023-07-04
Expiration Date
Abstract
The present invention relates to TLR7 agonists according to Formula I and their use in the treatment of diseases such as cancer and infectious disease.
Core Innovation
The invention provides compounds having the structure of Formula I, including stereoisomers, tautomers, and pharmaceutically acceptable salts. The Formula I scaffold defines substituents R1 through R8 and an integer n, with substituent options including H, OH, O-C(O)-R8, F, alkyl, cycloalkyl, aryl, and heteroaryl, together with optional substitutions and structural constraints including that at least one of R4 or R5 is not H. The disclosed subject matter includes purine-containing and tetrahydrofuran-linked scaffold variants, including fluorinated tetrahydrofuran-purine derivatives and deprotected amino/oxo derivatives such as purine-6,8-diones.
The description frames the compounds in relation to TLR7 biology and TLR7 agonism, including activation mediated through plasmacytoid dendritic cells and type I interferon, with downstream effects involving CD8+ cytotoxic T lymphocytes, antigen-presenting cells, dendritic cells, natural killer cells, and cytokines and chemokines such as TNF-alpha, IL-12, MIP-1alpha, and IP-10. It also describes a rationale for TLR7 activation without substantial TLR8 activation and notes a narrow therapeutic window for systemic dosing.
The document further describes synthetic examples and intermediates within the Formula I structural space, including acetyl-protected tetrahydrofuran intermediates, deprotection to amino-dione products, stereodefined intermediates, stereoisomeric variants, diastereomeric mixtures, and characterization data. Example compounds vary the tetrahydrofuran side chain substituents, including hydroxyethyl, hydroxypropyl, trifluoro-1-hydroxyethyl, fluoro-substituted tetrahydrofuran, propa-1,2-dien-1-yl, allenyl-type, prop-2-yn-1-yl, propyl, butyl, trifluoromethyl, trifluoropropyl, and cyclopropylmethyl substituents.
Therapeutic and prophylactic use is described for the Formula I compounds, including treatment and prevention of cancer and infectious diseases. The document also describes pharmaceutical compositions with pharmaceutically acceptable carriers and combination therapy with tumor vaccines, chemotherapies, radiation, targeted therapies, immune checkpoint and pathway modulators, and immune costimulatory and cytokine-pathway agents.
Claims Coverage
The independent claims cover a Formula I compound and methods for treating or preventing cancer or infectious disease using the compound. Across the claim set, coverage is based on a substituent-defined scaffold with stereoisomer, tautomer, and pharmaceutically acceptable salt embodiments, plus method claims narrowed to viral infections, specified named viruses, and optional combination with immune-modulating agents. The claims also include a dependent refinement fixing R8 to -CH3.
Formula I compound with defined substituent options
A compound having the structure of Formula I with substituents R1-R8 and integer n defined by specified substituent-type options, including H, OH, O-C(O)-R8, F, alkyl, cycloalkyl, aryl, heteroaryl, and other listed heteroatom-containing substituents, with at least one of R4 or R5 not being H, and including stereoisomers, tautomers, and pharmaceutically acceptable salts.
Fixed R8 substituent group
The Formula I compound is further specified with R8 set to -CH3, together with stereoisomers, tautomers, and pharmaceutically acceptable salts.
Treating or preventing cancer or infectious disease
A method for treating or preventing an infectious disease or cancer by administering an effective amount of one or more compounds having the structure of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to an individual.
Viral infection indication
The method of treating or preventing an infectious disease or cancer is specified for an infectious disease that is a viral infection.
Specified viral causes
The viral infection is caused by a virus selected from a specified group of named viruses, including HIV, hepatitis viruses A-D, VZV, HSV, CMV, Epstein Barr virus, adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, arboviral encephalitis virus, SARS-CoV, MERS, and SARS-CoV-2.
Combination with immune-modulating agents
The method further includes administering one or more additional immune-modulating agents selected independently from immune checkpoint inhibitors, OX40 agonists, 4-1BB agonists, ICOS agonists, GITR agonists, IL-2-receptor agonists, and antibodies mediated by ADCC.
The claims are anchored by a broad Formula I structural definition covering extensive R1-R8 and n substitution possibilities, with the constraint that at least one of R4 or R5 is not H and with stereoisomer, tautomer, and pharmaceutically acceptable salt coverage. The remaining claims add a fixed R8 embodiment and method claims for treating or preventing cancer or infectious disease, including viral infections caused by specified named viruses and optional combination with specified immune-modulating agents.
Stated Advantages
The document describes an objective to activate TLR7 without substantial TLR8 activation.
The background addresses challenges with systemic dosing due to a narrow therapeutic window.
Documented Applications
Treatment or prevention of cancer.
Treatment or prevention of infectious diseases.
Treatment or prevention of viral infections.
Use for viral infections caused by listed named viruses, including HIV and hepatitis viruses A-D.
Combination therapy with tumor vaccines, chemotherapies, radiation, targeted therapies, immune checkpoint and pathway modulators, and immune costimulatory and cytokine-pathway agents.
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