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-10941175-B2
Publication Date
2021-03-09
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 disclosure relates to compounds of Formula I and related embodiments, including Formula IA, Formula IB, and Formula II, together with pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, racemates, or mixtures thereof. The compounds are defined by variable substituents Ra, Rb, R1, R2, R3, R4, Rc, and n, with Rc independently H or -D and n independently 0, 1, 2, or 3. The document presents specific examples including Compound 1 and related derivatives, including Compound 1-triphosphate.
The compounds are presented as antiviral agents for viral infection and viral infection-associated disease/disorder, including norovirus infection. The disclosure includes pharmaceutical compositions and describes the compounds in connection with manufacture of a medicament for treating a viral infection and for disease treatment and prophylaxis. It also references dosing language for compounds across multiple ssRNA viruses, including norovirus.
The biological characterization focuses on activity against mouse norovirus (MNV/CR3) and includes conversion to the corresponding triphosphate, referred to as compound 1-TP. The document also describes phospholipid conjugates and a delivery rationale in which lipid conjugation is used to enhance uptake and intracellular activation. It further reports in vitro antiviral screening, cytotoxicity screening, and murine and human norovirus antiviral efficacy.
Claims Coverage
The consolidated claim coverage centers on formula-defined compound genera with extensive substituent variability, pharmaceutically acceptable salts/solvates, and stereochemical forms, together with antiviral treatment or prevention by administering an effective amount. The claim coverage reflects 7 inventive features in total.
Formula I compound with variable substituents
A compound of Formula I in which Ra, Rb, R1, R2, R3, R4, Rc, and n are defined by allowed substituent options, including optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups.
Pharmaceutically acceptable and stereochemical forms
The compound is provided as a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture thereof.
Discrete constraints for Rc and n
Rc is independently H or -D, and n is independently 0, 1, 2, or 3.
In vivo existence of the compound
The compound described is specified to exist in vivo.
Treatment or prevention of viral infection
A method that treats or prevents a viral infection by administering an effective amount of a compound of Formula I or its pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture to a subject in need.
Norovirus-specific viral indication
The viral infection is norovirus infection.
In vivo conversion to the defined compound
A method in which the administered compound is converted in vivo into a compound of Formula I or one of its pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or mixture forms.
The claims cover a formula-defined compound family with broad substituent options and explicit constraints for Rc and n, together with pharmaceutically acceptable salt, solvate, and stereochemical variants. The coverage extends to methods of treating or preventing viral infection, including norovirus infection, and includes an in vivo conversion variant.
Stated Advantages
Provides potent mouse norovirus activity for compound 1, with reported EC50 values.
Shows acceptable selectivity relative to cytotoxicity, with selectivity index (SI) reported.
Efficacy in mice with dose- and time-dependent reductions in murine norovirus titers.
Demonstrates in vitro norovirus polymerase inhibition with IC50/IC90 values reported.
Shows cellular conversion of compound 1 to its triphosphate (compound 1-TP) at a higher cellular level than the parent.
Comparative analog data indicate reduced activity when aryl amine/cyano variants are altered.
Documented Applications
In vitro antiviral screening and cytotoxicity assessment across multiple DNA/RNA viruses, with EC50/CC50/SI reporting.
Mouse norovirus (MNV/CR3) evaluation, including in vitro activity in RAW cells and in vivo efficacy in mice with reductions in murine norovirus titers.
Norovirus polymerase inhibition evaluation with IC50/IC90 values reported.
Cellular evaluation of conversion of compound 1 to compound 1-TP in relevant cellular context.
Use in treating or preventing norovirus infection in a subject by administration of an effective amount of a compound that is converted in vivo into the specified compound forms.
Treating viral infection.
Preventing viral infection.
Treating or preventing norovirus infection (human norovirus and murine norovirus are included in the document description).
Prophylactic use for viral infection.
Manufacturing a medicament for treating a viral infection, specifically norovirus.
Disease treatment and prophylaxis.
Pharmaceutical compositions and dosing for compounds of Formula I, Formula IA, Formula IB, and Formula II across multiple ssRNA viruses, including norovirus.
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