Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11059824-B2
Publication Date
2021-07-13
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 disclosure is directed to substituted purine TLR7 agonists of Formula I, including a substituent-variable scaffold defined by R1–R7, and includes pharmaceutically acceptable salts, solvates, and hydrates. The disclosure identifies specific example embodiments by named compounds and addresses tautomerism, including 1A/1B forms. The compounds act as TLR7 agonists with reduced TLR8 activation, compared to relevant references such as loxoribine.
The disclosure further describes the preparation of substituted purine and purine-tetrahydrofuran derivatives through multiple synthetic route schemes, including intermediates derived from guanosine nucleoside analogs and purine intermediates. The routes include halogenation and SNAr/ether formation, N-alkylation, transformations that change the R5 substituent including Cl/H/OCH3/SH, glycosylation to install the nucleoside sugar, and conversion through intermediate carbamates.
The work also describes synthetic preparation of multiple nucleoside-like purine derivatives and purine-tetrahydrofuran derivatives, including specific compounds and analogs with substituted purine cores and attachments to substituted tetrahydrofuran scaffolds. The disclosure includes conversion of benzyloxy-protected purine nucleoside diacetate intermediates through 6-chloro intermediates, deprotection, acetylation, POCl3-mediated ring functionalization, Pd/C hydrogenolysis, propargylation, and conversion to free 3-hydroxy and hydroxymethyl tetrahydrofuran motifs. Characterization data are provided, including HPLC purity, 1H NMR, ESI-MS, and ES+/ES− m/z, together with yields and analytical data.
Claims Coverage
The provided independent claims cover chemical compounds defined broadly by selected groups or by specified structures, with optional coverage of pharmaceutically acceptable salts, solvates, and hydrates. Across the provided independent claims, the inventive coverage is the compound definition itself plus allowable salt, solvate, and hydrate forms.
Compound selected from a group or pharmaceutically acceptable forms
A compound selected from the group consisting of an unspecified group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
Structurally defined compound or pharmaceutically acceptable forms
A compound having an unspecified structure, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
Structure-defined purine-tetrahydrofuran compound
A compound having the structure as specified in the claim, corresponding to the purine-tetrahydrofuran derivatives described in the document.
Nucleoside-like compound structure
A compound having the structure defined by a specified chemical formula, including the nucleoside-like purine derivatives described in the document.
The provided independent claims cover substituted purine TLR7 agonist compounds and related purine-tetrahydrofuran or nucleoside-like structures at a high level by either selecting compounds from an unspecified group or by defining compounds by an unspecified chemical structure, while expressly including pharmaceutically acceptable salts, solvates, and hydrates.
Stated Advantages
TLR7 agonist activity with reduced TLR8 activation.
Utility for treating and preventing cancer.
Utility for treating and preventing infectious disease.
Documented Applications
Evaluation of the compounds as TLR7 and TLR8 agonists using a HEK293-TLR7/8-NF-κB-SEAP reporter assay.
Interferon-α induction in hPBMCs with weighted MEC reporting.
Oral bioavailability assessment in cynomolgus monkeys, including percent bioavailability and related exposure metrics.
Antitumor activity testing in a rodent melanoma model (B16-F10), with tumor growth inhibition reported as percent TGI.
Treating and/or preventing cancer.
Treating and/or preventing infectious disease.
Interested in licensing this patent?