2′-substituted-N6-substituted purine nucleotides for RNA virus treatment
Inventors
Sommadossi, Jean-Pierre • Moussa, Adel
Assignees
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Publication Number
US-10946033-B2
Publication Date
2021-03-16
Expiration Date
Abstract
The use of described compounds or pharmaceutically acceptable salts or compositions thereof for the treatment of a host infected with an RNA virus other than HCV, or other disorder more fully described herein.
Core Innovation
The disclosure relates to stabilized phosphate prodrugs and thiophosphoramidate prodrugs for treating RNA virus infections in a host, including humans. The compounds are represented by multiple formula families, including Formulas I, II, III, IV, V, and VI and related subformulas, with extensive Markush definitions for substituent positions and stereochemical options, including phosphoramidate chirality, R/S, D/L configuration, and beta-D or beta-L isomers.
The prodrug structures include phosphoramidate and thiophosphoramidate motifs, with embodiments described as 5′- and 3′,5′-prodrugs capable of delivering mono-, di-, or triphosphates in vivo. The disclosure also includes stabilized phosphate thiophosphate or thiophosphoramidate scaffolds, fatty-alcohol derived and fatty-acid derived substituents, and cyclic thiophosphoramidate embodiments positioned within the nucleoside/furanose framework.
The compounds include fluorinated purine nucleoside/phosphoramidate compounds, nucleoside-like compounds containing a cyclopentane core, and aminopurine nucleoside/pro-nucleotide analogs. The therapeutic embodiments state administering an effective amount of the compounds, or pharmaceutically acceptable salts thereof, to treat RNA virus infections, including Dengue Fever and flavivirus infection.
Claims Coverage
The consolidated independent claim coverage centers on administering an effective amount of a compound of a specified formula, or a pharmaceutically acceptable salt thereof, for treating Dengue Fever in a host or a human. Across the independent claims, the inventive features are the treatment indication, the formula-defined compound scaffold, and in one claim the specific substituent constraints for R7 through R11.
Dengue fever treatment by administering a formula-defined compound with constrained substituents
A method to treat a host infected with Dengue Fever comprising administering an effective amount of a compound of the formula, or a pharmaceutically acceptable salt thereof, wherein R7 is C1-6 alkyl, C3-7 cycloalkyl, or aryl; R8 is hydrogen or C1-6 alkyl; R9a and R9b are independently selected from hydrogen, C1-6 alkyl, cycloalkyl, aryl and aryl(C1-3 alkyl)-; R10 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C3-7 cycloalkyl; and R11 is C1-6 alkyl, cycloalkyl, C2-6 alkynyl, C2-6 alkenyl, or acyl.
Human dengue fever treatment by administering an effective amount of a formula compound
A method to treat a human infected with Dengue Fever comprising administering an effective amount of a compound of the formula, or a pharmaceutically acceptable salt thereof, to treat the human in need thereof.
Dengue fever subtypes and stereochemical narrowing
Dependent claim refinements specify Dengue fever 2 and Dengue fever 3, and some refinements specify the L-configuration of the phosphoramidate.
Collectively, the independent claims require administering an effective amount of a compound of a specified formula, or a pharmaceutically acceptable salt thereof, to treat Dengue Fever in a host or in a human. One independent claim further constrains substituent classes for R7 through R11, and dependent claims further narrow the indication to Dengue fever 2 and Dengue fever 3 and, in some claim-family descriptions, specify stereochemical configuration.
Stated Advantages
Stabilized phosphate prodrugs/phosphoramidates can deliver mono/di/triphosphates in vivo.
Metabolic conversion leads to monophosphate/triphosphate formation for specific beta-D-2′-deoxy-2′alpha-fluoro-2′beta-C-substituted nucleotides.
Treatment of RNA virus infection in a host, including a human.
The disclosure reports yields and characterization data including 1H NMR, 31P NMR, and MS (ESI).
Compound 205 is reported as the most potent among the reported tested compounds in the partial content, with EC50 values of 0.8 μM for DENV-2 and 1.2 μM for YFV.
Documented Applications
Treatment of RNA virus infection in a host, including a human.
Treatment of a host infected with Dengue Fever by administering an effective amount of a compound of the formula, or a pharmaceutically acceptable salt thereof.
Treatment of a human infected with Dengue Fever by administering an effective amount of a compound of the formula, or a pharmaceutically acceptable salt thereof.
Treatment of Dengue fever 2 and Dengue fever 3 in dependent claim contexts.
Biological testing reporting EC50 activity against Dengue virus type 2 (DENV-2) and Yellow Fever virus (YFV) in BHK21 cells using XTT-based cell viability/CPE reduction assays.
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