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Publication Number
US-12037335-B2
Publication Date
2024-07-16
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, or pharmaceutically acceptable salts, solvates, or hydrates thereof. The compounds are defined by substituent variables R1, R2, R3, R4, R5, R6, R7, and R8, with variable ranges including alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl portions, and optional substitution patterns on the selected hydrocarbon, cycloalkyl, heterocyclyl, aryl, or heteroaryl portions. The subject matter also includes 9-β-furano-purine nucleoside analogs of Formula I and related purine structures, including substituted purine intermediates and 2-amino-6-chloro-7-alkyl-7,9-dihydro-8H-purin-8-ones.
The therapeutic context describes TLR7 agonist compounds and selective activation of TLR7 without substantial TLR8 activation. The disclosure relates the compounds to immunological outcomes including stimulation of interferon (IFN)-alpha and activation relevant to plasmacytoid dendritic cells, and connects these structures to cancer and infection contexts. The text also includes pharmaceutical compositions with a pharmaceutically acceptable excipient and additional immunomodulatory agents or immune checkpoint-related inhibitors.
The disclosure further includes discussion of tautomerism and example compound structures, representative Formula I compounds, defined intermediate compounds, and specific substituted purine structures supported by analytical data. Overall, the compound family is defined by Formula I structures with variable substituents and pharmaceutically acceptable salts, solvates, or hydrates.
Claims Coverage
The consolidated claim coverage centers on a Formula I compound scaffold with variable substituents across R1-R8 and an integer n = 1, 2, 3, 4, or 5, and includes pharmaceutical compositions and enumerated specific substituted purine structures. The inventive scope includes 4 broad inventive features.
Formula I TLR7 agonist compound structure
A compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate, with R1, R2, R3, R4, R5, R6, R7, and R8 defined as substituent variables and n as an integer 1, 2, 3, 4, or 5.
Optional substitution patterns on hydrocarbon chains, aryl, and heteroaryl
Optional substitution on selected alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl portions with substituents including halogen, CN, NO2, carbonyl-containing groups, alkoxy/alkyl oxy groups, thio and sulfonyl groups, and amino/amido groups.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate, together with a pharmaceutically acceptable excipient.
Enumerated substituted purine compounds
A set of specific substituted purine compounds, including pharmaceutically acceptable salt, solvate, and hydrate forms, selected from an enumerated group of defined molecular structures.
The claims cover a broad Formula I substituted compound scaffold with defined R-group scope and optional substitution patterns, and extend to pharmaceutical compositions and enumerated specific substituted purine compound structures.
Stated Advantages
Selective activation of TLR7 without substantial TLR8 activation.
Stimulation of interferon (IFN)-alpha.
Substantially greater systemic delivery for prodrug forms of parent compounds 1, 26, and 27 versus loxoribine, as measured by oral bioavailability in cynomolgus monkeys.
Compounds show TLR7 agonist activity in HEK293-TLR7/8-SEAP cells and interferon-alpha activity in hPBMCs, with no significant TLR8 activity up to 500 μM for the selected compounds described.
Antitumor activity is reported for compound 5 in a B16-F10 rodent melanoma model, with reported tumor growth inhibition for IV regimens compared to controls.
Documented Applications
Treating infections.
Treating immune disorders.
Treating cancer.
TLR7 agonist activity assessment in HEK293-TLR7/8-SEAP cells using EC50 values.
Interferon-alpha induction assessment in hPBMCs using weighted MEC values.
Oral bioavailability evaluation in cynomolgus monkeys, including comparison of prodrug forms versus loxoribine.
Antitumor application in a B16-F10 rodent melanoma tumor model, including tumor growth inhibition for IV regimens versus controls.
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