2′-substituted-N6-substituted purine nucleotides for RNA virus treatment
Inventors
Sommadossi, Jean-Pierre • Moussa, Adel
Assignees
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Publication Number
US-11975016-B2
Publication Date
2024-05-07
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 thiophosphoramidate compounds and related thiophosphoramidate-phosphoramidate-like nucleoside pronucleotides and nucleoside derivatives using representative Formula IIIe. The structures are defined by substituent variables including Y, R1, R2, R3, R7, R8, R9a, R9b, and R10, with stereochemical and positioning concepts including 5′-position and 3′-position thiophosphoramidate on a furanose ring and cyclic thiophosphoramidate via 5′ attachment to a 3′-OH.
The compounds are framed as stabilized phosphate prodrugs of RNA-virus antiviral nucleoside derivatives and as 2′-substituted N6-substituted purine nucleotide prodrugs intended for use as pharmaceutical compositions for treating RNA viruses. The description includes stereochemical considerations distinguishing β-D versus β-L isomers, phosphorous R/S configurations, and stereochemical purity as being 90-100% free of the opposite enantiomer.
The invention relates the defined Formula IIIe compounds to treatment use against viruses selected from yellow fever, West Nile, Zika, and Japanese B encephalitis by administering an effective amount of the compound or a pharmaceutically acceptable salt. The disclosed compound variables constrain substituent choices to provide a targeted set of prodrug structures within the Formula IIIe framework, and the embodiments include stabilized phosphate prodrug families, including phosphoramidate and thiophosphoramidate forms and mono-, di-, and triphosphate-related forms.
Claims Coverage
The claim coverage centers on a method of treating a human host infected with a selected RNA virus by administering an effective amount of a compound Formula IIIe or a pharmaceutically acceptable salt thereof. The independent inventive concept is defined by the virus selection set and explicit Formula IIIe substituent constraints, while the broader disclosure also refers to stabilized phosphate prodrugs and thiophosphoramidate forms.
Treatment of a human host with Formula IIIe prodrugs for specified viral infections
A method of treating a human host infected with a virus selected from the group consisting of yellow fever, West Nile, Zika, and Japanese B encephalitis by administering an effective amount of a compound of Formula IIIe or a pharmaceutically acceptable salt thereof.
Formula IIIe substituent-variable constraints defining the compound
The compound of Formula IIIe is defined such that Y is NR1R2, R1 is methyl, R2 is hydrogen, R3 is hydrogen, R7 is heteroaryl or aryl, R8 is hydrogen or C1-6 alkyl, R9a and R9b are independently selected from hydrogen and C1-6 alkyl, and R10 is C1-6 alkyl.
Overall, the claim coverage focuses on treating a human host infected with one of the specified viruses by administering an effective amount of a Formula IIIe compound, with the scope defined by explicit substituent-variable constraints.
Stated Advantages
Improved activity and therapeutic index via stabilized phosphate prodrugs that are metabolically activated to a nucleotide 5′-monophosphate and ultimately an active 5′-triphosphate.
Treating an RNA virus infection in a host, including a human.
Therapeutically treats infections of RNA viruses in a host, including humans.
Documented Applications
Treating human host infections caused by RNA viruses selected from yellow fever, West Nile, Zika, and Japanese B encephalitis, using compounds of Formula IIIe or pharmaceutically acceptable salts.
Therapeutic treatment of human hosts infected with RNA viruses, including yellow fever, West Nile, Zika, and Japanese B encephalitis.
Treating a human host in need thereof infected with a virus selected from yellow fever, West Nile, Zika, and Japanese B encephalitis.
Treating infections of RNA viruses in a host, including humans.
Using thiophosphoramidate and other stabilized phosphate prodrugs as effective-amount therapeutics for treating RNA-virus infections in a host, including humans.
Antiviral activity testing of selected compounds against Dengue virus type 2 (DENV-2) and Yellow Fever (YFV) using an XTT-based measurement of virus-induced CPE/cell viability in BHK21 cells, with results reported as EC50 values.
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