Spirothietane nucleosides
Inventors
Tahri, Abdellah • Bonfanti, Jean-François • Jonckers, Tim Hugo Maria • Raboisson, Pierre Jean-Marie Bernard
Assignees
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Publication Number
US-11267844-B2
Publication Date
2022-03-08
Expiration Date
Abstract
The present invention relates to 2′-spirothietane nucleosides, and the phosphates and the prodrugs thereof, and the pharmaceutically acceptable salts and solvates thereof, and the use of such compounds as a medicament, in particular in the prevention and/or treatment of viral infections caused by viruses belonging to the Flaviviridae family and/or to the alphavirus genus. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, and to the compositions or preparations for use as a medicament, more preferably for the prevention or treatment of viral infections caused by viruses belonging to the Flaviviridae family and/or to the alphavirus genus. The invention also relates to processes for the preparation of the compounds.
Core Innovation
The patent defines compounds of Formula (I) or Formula (I′), or stereoisomeric forms thereof, with extensive substituent definitions, optional substitution patterns, and ring-forming constraints. The structures include specified Base selections, pharmaceutically acceptable salts and solvates, phosphates, prodrugs, and phosphoramidate group variants, together with stereochemically defined 5′-monophosphate, 5′-diphosphate, and 5′-triphosphate ester forms.
The disclosure includes fluorinated bicyclic, tetracyclic, spiro-thiaspiro, and spirothietane nucleoside-related compounds, including phosphonate moieties and thietane/thio motifs. The structural scope also covers phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, and indolyl variants, with cases in which substituent groups form C3-C7 cycloalkanediyl, 3- to 7-membered heterocyclic rings containing one oxygen atom, azetidinyl, pyrrolidinyl, or piperidinyl rings.
The compounds are presented for antiviral evaluation and antiviral use against Flaviviridae and alphaviruses, including hepatitis C virus, dengue virus, chikungunya virus, Sindbis virus, and Simliki Forest virus. The document also contemplates pharmaceutical compositions and combination preparations with additional antivirals, and includes assay concepts such as HCV replicon luciferase, resazurin, DENV phenotypic assay with eGFP readout, dengue polymerase inhibition, and CHIKV CPE inhibition assay [procedural detail omitted for safety].
Claims Coverage
The consolidated claim coverage centers on two highly constrained compound definitions, Formula (I) and Formula (I′), each with extensive Base, substituent, and ring-forming limitations. Across the items, the independent claims also cover a pharmaceutical composition containing a therapeutically effective amount of the claimed compound and a method of treating a warm-blooded animal infected with Flaviviridae and/or alphavirus. In total, the claim set contains multiple inventive features centered on the defined compound structures and their pharmaceutical and therapeutic use.
Formula (I) compound with specified Base and substituent constraints
A compound of Formula (I) or a stereoisomeric form thereof, wherein Base is selected from (B-1), (B-2), (B-3a), (B-3b), (B-4) and (B-5); R is hydrogen or C1-6 alkyl; R1 is selected from hydrogen and groups of formula (a-1) to (a-4); R4 and R7 are each independently selected from the listed aromatic/heteroaromatic options, including optionally substituted indolyl; and the claim includes divalent radical formation ((c-1) or (c-2)) and ring-forming constraints including azetidinyl, pyrrolidinyl, or piperidinyl ring options.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition including a therapeutically effective amount of the compound of Formula (I) together with a pharmaceutically acceptable carrier.
Antiviral treatment method for warm-blooded animals infected with Flaviviridae and/or alphavirus
A method of treating a warm-blooded animal infected with Flaviviridae and/or alphavirus by administering an anti-Flaviviridae and/or anti-alphavirus effective amount of the compound of Formula (I).
Formula (I′) compound with defined Base and substituent sets
A compound of Formula (I′) or a stereoisomeric form thereof, wherein Base is selected from the group consisting of (B-1), (B-2), (B-3a), (B-3b), (B-4) and (B-5), and wherein R is hydrogen or C1-6 alkyl; R1 is hydrogen or a group of formula (a-1), (a-2), (a-3), or (a-4); and R4 and R7, together with further named variables, are selected from explicitly defined aromatic, heteroaromatic, alkyl, amino, and ring-forming options, including pharmaceutically acceptable salts or solvates thereof.
Further structural refinement by Base narrowing and R3 selection
The compound of claim 1 is defined such that Base is (B-1), (B-2), or (B-3a) and R3 is selected from hydrogen, halo, and N3.
Structural constraints for R1 via hydrogen, formula (a-1), or divalent radical formation
The compound of claim 1 is defined further by specifying that R1 is selected from hydrogen or a group of formula (a-1), or that R1 and R2 together form a divalent radical of formula (c-2).
Pharmaceutical composition comprising the claimed compound
A pharmaceutical composition includes a therapeutically effective amount of the compound of claim 1 together with a pharmaceutically acceptable carrier.
Antiviral treatment method for warm-blooded animals infected with Flaviviridae and/or alphavirus
A method of treating a warm-blooded animal infected with Flaviviridae and/or alphavirus by administering an anti-Flaviviridae and/or anti-alphavirus effective amount of a compound of Formula (I) (as defined in claim 1).
The claim set is anchored by Formula (I) and Formula (I′) compounds defined by extensive Base and substituent constraints, with dependent claims narrowing specific Base, R3, and R1 options and including divalent-radical and ring-forming limitations. Protection also extends to a pharmaceutical composition containing a therapeutically effective amount and to antiviral treatment of warm-blooded animals infected with Flaviviridae and/or alphavirus.
Stated Advantages
High enantiomeric purity at fixed chirality centers.
Antiviral potency is assessed in cellular antiviral assays and biochemical polymerase inhibition assays while cytotoxicity is assessed in counterscreens.
Antiviral activity of Formula (I) compounds against Flaviviridae and alphaviruses, including HCV, dengue virus, chikungunya virus, Sindbis virus, and Simliki Forest virus.
Use in treatment and prevention is stated for the pharmaceutical compositions and methods described.
Documented Applications
Cellular antiviral assays using an HCV replicon luciferase-based replicon assay to derive EC50 values.
Phenotypic dengue assays in Vero and Huh-7 cells using eGFP readout and cytotoxicity counterscreens.
Additional dengue NS5 polymerase inhibition and CHIKV CPE inhibition assays.
Biochemical polymerase inhibition data including HCV/DENV2 IC50 values.
Antiviral evaluation using an HCV replicon luciferase assay, DENV phenotypic assay with eGFP readout, dengue polymerase inhibition, and CHIKV CPE inhibition assay [procedural detail omitted for safety].
Treatment and prevention of infections in warm-blooded animals with Flaviviridae and/or alphaviruses by administering a compound of Formula (I).
Use as a therapeutically effective pharmaceutical composition together with a pharmaceutically acceptable carrier.
Manufacture and use of medicaments in connection with the antiviral compounds.
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