Compounds
Inventors
Hunt, Simon Fraser • Onions, Stuart Thomas • Sherbukhin, Vladimir • FORDYCE, EUAN ALEXANDER FRASER • THOMAS, Jennifer Claire • Murray, Peter John • COATES, Matthew Stephen • BROOKES, Daniel William • Ito, Kazuhiro • Strong, Peter
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10626126-B2
Publication Date
2020-04-21
Expiration Date
Abstract
There are provided 5,6-dihydro-4H-dithieno[3,2-b:2′,3′-d]azepine derivatives(as defined in the disclosure) which are useful in the treatment of RSV infection and for the prevention of disease associated with RSV infection.
Core Innovation
The invention relates to compounds of formula (I) with a pyridine-based scaffold, and to 5,6-dihydro-4H-dithieno[3,2-b:2′,3′-d]azepine derivatives. The compounds are defined by broadly variable substituents R, R1-R5, and integers m and n, with alternative scaffold embodiments and either independent R1 and R2 selections or a fused bicyclic system comprising a 5- or 6-membered carbocyclic or heterocyclic ring containing heteroatoms selected only from O and S fused to the pyridine nucleus.
The document also covers pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, polymorphs, and stable isotopes/deuterium forms. It further describes example compounds containing pyridine/hetero-fused scaffold variants, including systems with benzoyl/nicotinamido substituents and spiro/pyrano/cycloalkyl fused configurations.
The disclosure identifies RSV A and B strains and frames the compounds as RSV therapeutic compounds for prophylactic and therapeutic control of RSV infection. Biological data show inhibition of RSV cytopathic effect, virus replication, and F-protein expression, including potency against RSV A/B and long lung duration of action.
Claims Coverage
The independent claim set includes one independent compound claim and one independent use claim. The claim coverage centers on broad pyridine-based formula (I) compounds with alternative R1/R2 definitions including a fused bicyclic system, pharmaceutically acceptable salts, and use for treating RSV by administering an effective amount.
Pyridine-based compound of formula (I) with broadly defined substituents
A compound of formula (I) wherein R represents hydrogen or halo; R3, R4, and R5 are independently selected from the enumerated groups; and m and n are integers independently selected from 1 and 2.
Two alternative R1/R2 substitution regimes
Either R1 and R2 are independently selected from hydrogen and specified groups, or R1 and R2 are in positions 6 and 5 of the pyridine nucleus and are joined to form a bicyclic system comprising either a 5- or 6-membered carbocyclic ring or a 5- or 6-membered heterocyclic ring containing heteroatoms selected only from O and S, fused to the pyridine nucleus.
Pharmaceutically acceptable salts
The compound of formula (I) includes pharmaceutically acceptable salts thereof.
RSV treatment by administering an effective amount
A method of treating a subject infected with RSV by administering an effective amount of a compound according to claim 1.
Overall, the claims coverage centers on the formula (I) pyridine-based scaffold with broadly defined substituents, the fused O/S-containing bicyclic variant, pharmaceutically acceptable salts, and RSV treatment by administering an effective amount.
Stated Advantages
Potent inhibition of RSV cytopathic effect, virus replication, and F-protein expression.
Potency against RSV A/B.
Long lung duration of action.
Once-daily dosing.
Acceptable safety after topical lung or nose administration.
Potent RSV inhibition with low cytotoxicity is highlighted for Example 1.
Inhibition of RSV F-protein expression in BEAS2B cells is reported.
Antiviral effects in human primary bronchial air-liquid interface cultured epithelial cells are reported.
In vivo efficacy in cotton rats is reported, including lung virus titre and gene expression.
Documented Applications
Prophylactic and therapeutic use for RSV infection in at-risk subject populations including premature infants, subjects with congenital lung or heart defects, immunocompromised subjects including HIV, elderly subjects, and subjects with congestive heart failure or COPD.
Treatment of a subject infected with RSV by administering an effective amount of a compound according to formula (I).
Topical pulmonary/intranasal delivery, including aerosols, suspensions, and dry powder formulations.
Combination therapy or co-formulation with other anti-RSV or anti-inflammatory agents, including palivizumab, RNA polymerase inhibitors, ribavirin, and other anti-inflammatory agents.
RSV inhibition, including CPE inhibition in HEp2 cells and inhibition of RSV F-protein expression in BEAS2B cells.
Antiviral effects in human primary bronchial air-liquid interface cultured human bronchial epithelial cells.
In vivo efficacy against RSV in cotton rats, including lung virus titre and gene expression.
Interested in licensing this patent?