Dihydrofuropyridine derivatives as rho-kinase inhibitors
Inventors
RANCATI, Fabio • Accetta, Alessandro • Capelli, Anna Maria • PALA, Daniele • Edwards, Christine • PASQUA, Adele Elisa • Kapadnis, Prashant Bhimrao • Cheguillaume, Arnaud Jean Francois Auguste
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12534474-B2
Publication Date
2026-01-27
Expiration Date
Abstract
The invention relates to compounds of formula (I) inhibiting Rho Kinase that are dihydrofuropyridine derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. Particularly the compounds of the invention may be useful in the treatment of many disorders associated with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).
Core Innovation
The document describes compound(s) of formula (I) in which X1, X2, X3 and X4 are CH or N under defined constraints, with p being zero or an integer from 1 to 4, and with R options including (C1-C6)alkyl and halogen. R1 is pyridinyl, optionally substituted by selected groups, and L is defined as either -C(O)NH- or -NHC(O)-. The variables n, R2, R3, R4 and R5 are defined through sets of allowed atom types and substituent classes, including heteroaryl and heterocycloalkyl options.
The patent characterizes a specific benzamide-containing scaffold corresponding to the formula (I), including the embodiment N-(2-(Piperidin-4-yl)ethyl)-3-(((7-(pyridin-4-yl)-2,3-dihydrofuro[3,2-c]pyridin-4-yl)amino)methyl)benzamide and related analogs. The described intermediates include Intermediate J1 and Intermediate J2, and additional target molecules are obtained in the same chemical family.
The patent describes ROCK (ROCK-I/ROCK-II) as a therapeutic target and defines a dihydrofuropyridine/2,3-dihydrofuro[3,2-c]pyridine derivative scaffold of formula (I), including preferred formula (Ia). The disclosed compounds include enantiomers, diastereoisomers and mixtures thereof in any proportion, pharmaceutically acceptable salts and solvates, and also deuterated derivatives, polymorphs and atropisomers.
Claims Coverage
The provided claims center on compounds of formula (I) defined by constrained structural variables, with additional claim scope extending to pharmaceutical compositions, inhalable formulations, devices, and pharmaceutical combinations. Multiple inventive features are set out across the claim set.
Compound of formula (I)
A compound of formula (I) wherein X1, X2, X3 and X4 are all CH or one of X1, X2, X3 and X4 is N and the others are CH; p is zero or an integer from 1 to 4; each R, when present, is selected from (C1-C6)alkyl and halogen in each occurrence independently selected from F, Cl, Br and I; R1 is pyridinyl, optionally substituted by one or more groups selected from halogen, —(CH2)nNR4R5, and (C1-C6)alkyl; L is —C(O)NH— or —NHC(O)—; n is in each occurrence independently 0 or an integer selected from 1, 2 or 3; R2 and R3 are in each occurrence independently selected from the group consisting of —H, halogen, —OH, —(CH2)nNR4R5, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)haloalkoxy (C1-C6)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl and (C3-C6)heterocycloalkyl, each optionally substituted as defined; R4 and R5 are selected from —H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C3-C6)heterocycloalkyl; R6 and R7 are independently selected from —H and (C1-C6)alkyl; or a single enantiomer, diastereoisomers and mixtures thereof in any proportion or pharmaceutically acceptable salts and solvates thereof.
Pharmaceutical composition including carriers or excipients
The pharmaceutical composition includes the compound, including its enantiomer and diastereoisomers, or pharmaceutically acceptable salts/solvates, mixed with one or more pharmaceutically acceptable carriers or excipients.
Inhalable pharmaceutical composition formulation types
A pharmaceutical composition is formulated in an inhalable form selected from inhalable powders, propellant-containing metering aerosols, or propellant-free inhalable formulations.
Inhalation device for the inhalable formulation
A device that uses the pharmaceutical composition and specifies the device as a single- or multi-dose dry powder inhaler, a metered dose inhaler, or a soft mist nebulizer.
Pharmaceutical combination with selected active ingredients
A pharmaceutical combination includes the compound, or its enantiomer, diastereoisomer, pharmaceutically acceptable salts and solvates, together with one or more active ingredients selected from specified drug classes including organic nitrates/NO donors, inhaled NO, sGC stimulators, prostacyclin-related agents, cGMP/cAMP degradation inhibitors, neutrophilic elastase and neutral endopeptidase inhibitors, signaling inhibitors, blood-pressure lowering agents, osmotic agents, ENaC blockers, anti-inflammatories/antihistamines/anti-tussives, antibiotics and DNase and cleavage agents, inhibitors of ALK5 and/or ALK4 phosphorylation of Smad2 and Smad3, TPH1 inhibitors, and multi-kinase inhibitors.
The claim coverage is centered on compounds of formula (I) with tightly defined heteroatom substitution and benzamide linkage options, together with salts, solvates, stereoisomeric forms, and related scaffold definitions. Additional scope covers pharmaceutical compositions with carriers or excipients, inhalable formulation types, inhalation devices, and pharmaceutical combinations with selected active ingredient classes.
Stated Advantages
Compounds show Ki <500 nM (preferably <=60 nM, and sometimes <=3 nM).
Compounds are categorized for selectivity using PKA/ROCK2 ratio categories compared to ROCK2.
Documented Applications
Therapeutic use for pulmonary diseases including asthma, COPD, IPF, pulmonary hypertension (PH), and pulmonary arterial hypertension (PAH).
Therapeutic use via medicament use and disease-modifying prevention/treatment concepts, including administration by inhalation or oral routes.
Combination therapy in conjunction with listed active ingredient classes (as a pharmaceutical combination) for the above therapeutic context.
Interested in licensing this patent?