Arenavirus growth inhibitor comprising polycyclic carbamoyl pyridone derivative
Inventors
Ishii, Akihiro • Sato, Akihiko • Kawai, Makoto • Taoda, Yoshiyuki
Assignees
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Publication Number
US-12098151-B2
Publication Date
2024-09-24
Expiration Date
Abstract
The present invention provides a compound having antiviral activity, especially having arenavirus proliferation inhibitory activity, and/or a medicament comprising the compound. More preferably, the present invention provides a compound having proliferation inhibitory activity on the Old World arenaviruses such as Luna virus, Lassa virus, and lymphocytic choriomeningitis virus and/or the New World arenaviruses such as Junin virus, and/or a medicament comprising the compound.An arenavirus proliferation inhibitor comprising a compound represented by Formula (I) or a prodrug thereof or a pharmaceutically acceptable salt thereof: (wherein R1 is carboxy, or the like: A3 is CR2 or N; R2 is a hydrogen atom, halogen, hydroxy, or the like; R3 is a hydrogen atom, hydroxy, carboxy, cyano, formyl, alkyl optionally substituted with Substituent group F, or the like; either A1 or A2 is CR5R6, and the other is NR7, or A1 is CR8R9, and A2 is CR10OR11; and R5, R6, R7, R8, R9, R10, and R11 are each independently a hydrogen atom, carboxy, cyano, alkyl optionally substituted with Substituent group F, or the like).
Core Innovation
The invention relates to compounds represented by Formula (II), or prodrugs thereof, or pharmaceutically acceptable salts thereof. The compounds are defined by structural variables including Z, -L-, Ring A, R1a, R2a, R3a, R3b, R5a, R6a, R7a, R12a, R9, R10, R14, R15, n, and t, with substituent-group-controlled variability through Substituent group A, Substituent group B, Substituent group E, and Substituent group F.
Z is a single bond or a linear or branched alkylene, and -L- is -(CR3aR3b)n- or a single bond, with n being an integer of 1 to 4 and t being an integer of 0 to 4. Ring A is a non-aromatic carbocycle, an aromatic carbocycle, a non-aromatic heterocycle, or an aromatic heterocycle, and R5a and R6a may be taken together with the carbon atom to which they are attached to form a carbocycle or a heterocycle optionally substituted with Substituent group B, including condensed and/or bridged structures.
R9 and R10 may be taken together with an adjacent atom to form a heterocycle. The disclosure also includes provisos and an exclusion of a specified compound, and it is directed toward arenavirus-proliferation inhibition compounds in connection with treating, preventing, or ameliorating arenavirus-induced diseases, including Lassa fever.
Claims Coverage
The consolidated claim coverage centers on one main independent Formula (II) compound claim, with dependent refinements and additional pharmaceutical composition and use claims. The independent chemical claim includes multiple inventive features, including substituent-group-controlled structural definitions, ring and linker definitions, optional heterocycle formation, and a proviso excluding a specified compound.
Formula (II) compound scope with prodrugs and pharmaceutically acceptable salts
A compound represented by Formula (II) or a prodrug thereof or a pharmaceutically acceptable salt thereof, defined by Z, -L-, Ring A, R1a, R2a, R3a, R3b, R5a, R6a, R7a, R12a, R9, R10, R14, R15, n, and t, with substituent-group-controlled variability through Substituent group A, Substituent group B, Substituent group E, and Substituent group F.
Heterocycle formation from adjacent atoms
R9 and R10 may be taken together with an adjacent atom to form a heterocycle.
Condensed and bridged ring formation from R5a and R6a
R5a and R6a may be taken together with the carbon atom to which they are attached to form a carbocycle or a heterocycle, and the resulting ring may form a condensed ring and/or a bridged structure.
Ring A and linker definitions
Ring A is selected from a non-aromatic carbocycle, an aromatic carbocycle, a non-aromatic heterocycle, or an aromatic heterocycle, and -L- is defined as -(CR3aR3b)n- or a single bond, with n being an integer of 1 to 4.
Proviso-based R7a limitation and exclusion
A proviso limits R7a to a carbocyclic group or heterocyclic group optionally substituted with Substituent group B under the stated condition, and excludes a specified compound.
Pharmaceutical composition with carrier or diluent
A pharmaceutical composition including the compound or its prodrug and a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluent.
Method of inhibiting arenavirus proliferation by administration
A method of inhibiting arenavirus proliferation by administering an effective amount of a specified compound or its prodrug or pharmaceutically acceptable salt to a patient, an animal, or in vitro.
The claims cover a structurally defined Formula (II) compound family with prodrug and salt scope, optional heterocycle formation, and ring systems that may be condensed and/or bridged. The claim set also extends to pharmaceutical compositions and to methods for inhibiting arenavirus proliferation by administration of an effective amount.
Stated Advantages
High arenavirus (Old World and New World) proliferation inhibitory activity.
Metabolic stability is stated as an advantage.
Solubility is stated as an advantage.
Bioavailability is stated as an advantage.
Clearance is stated as an advantage.
Tissue migration is stated as an advantage.
Long half-life is stated as an advantage.
Low hERG/CYP inhibition is stated as an advantage.
Low genotoxicity/phototoxicity is stated as an advantage.
Documented Applications
Treatment, prevention, or amelioration of arenavirus-induced diseases, notably Lassa fever.
Inhibition of arenavirus proliferation by administering an effective amount to a patient, an animal, or in vitro.
Use of the specified compounds as pharmaceutical compositions including a pharmaceutically acceptable carrier or diluent.
In vitro inhibition of arenavirus proliferation, including CPE inhibition against Junin virus and LCMV.
Plaque-based proliferation inhibition results for Lassa virus are documented.
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