Pyrrolopyrimidine nucleosides and analogs thereof
Inventors
Bougher, III, John Henry • Changalvala, Ramamurty V S • Downey, Aaron Leigh • Drach, John C. • Lanier, Jr., Ernest Randall • McIver, Andrew Louis • Robertson, Bradley David • Selleseth, Dean Wallace • Sethna, Phiroze Behram • Townsend, Leroy • Ware, Roy W.
Assignees
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Publication Number
US-11981700-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present disclosure provides pyrrolopyrimidine nucleoside analogs of the Formula I, Formula IA, Formula IB, or Formula II and phospholipid conjugates and pharmaceutical compositions thereof wherein Rc and A are defined herein. Also presented are methods of treating and/or preventing viral infection and/or viral infection-associated disease or disorder with one or more compounds of Formula I, Formula IA, Formula IB, or Formula II.
Core Innovation
The invention relates to antiviral pyrrolopyrimidine nucleoside analogs comprising phospholipid conjugate A groups. The chemical structures are defined by Formula I, Formula IA, Formula IB, and Formula II, including variable substituents such as Rc, A, X1 to X3, and R/Ri/RIA/RIB/RII. The disclosure further encompasses pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, racemates, mixtures thereof, and stereochemical and isotopic variants.
The disclosure further includes phosphonate and triphosphate variants, including a specific nucleoside-like compound described as Compound 1 together with its triphosphate form (Compound 1-TP/PPP). It presents antiviral evaluation and cytotoxicity readouts for disclosed compounds, including efficacy in relation to mouse norovirus, cellular conversion information consistent with formation of a triphosphate form in cells, and selectivity discussed using EC50, CC50, and SI across multiple viruses.
The invention addresses viral infection treatment or prevention using the disclosed compounds, including norovirus and ssRNA viruses such as norovirus. The disclosure further includes pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers, and states administration methods for delivering the compounds as part of therapeutic or preventive use.
Claims Coverage
The provided claim material covers compound definitions with pharmaceutically acceptable variants and explicit enumerated compound identities, and includes a pharmaceutical composition embodiment. Three inventive features are identified.
Phospholipid-conjugated antiviral pyrrolopyrimidine nucleoside analog compound forms
A compound defined by the stated compound-number embodiments, including pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture forms.
Enumerated compound identity with pharmaceutically acceptable variants
The compound is selected from the stated compound-number values, including compound no. 7, 9, 56, 66, 127, 130, 134, 129, and 136, each optionally in pharmaceutically acceptable form variants.
Pharmaceutical composition comprising the compound with carrier
A pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
Overall, the claims are directed to a defined compound scaffold in multiple explicit compound-number embodiments and to pharmaceutically acceptable variants, with additional coverage to pharmaceutical compositions containing the compound plus a pharmaceutically acceptable carrier.
Stated Advantages
Improve delivery.
Increase intracellular formation of active monophosphate/triphosphate antiviral species.
The compounds are useful as medicaments for treating viral infections, specifically norovirus.
Antiviral activity and selectivity are documented across multiple viruses.
Comparative potency versus other analogs is documented for Compound 1.
Documented Applications
Treating or preventing viral infections, including norovirus and ssRNA viruses such as norovirus.
Pharmaceutical compositions for therapeutic and preventive use of the disclosed compounds.
Combination therapy concepts and dosage regimens in the pharmaceutical composition context.
Antiviral activity against mouse norovirus is documented for Compound 1.
Cellular conversion to a triphosphate form is documented using RAW cells.
Antiviral activity evaluation is reported across multiple viruses, including influenza virus (H1N1), RSV, SARS-CoV, Dengue (DENV), West Nile virus (WNV), Yellow fever virus (YFV), and Rift Valley fever virus (RVFV).
In vitro and in vivo efficacy for Compound 1 are reported [procedural detail omitted for safety].
Medicaments for treating viral infections, specifically norovirus.
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