sGC stimulators
Inventors
Nakai, Takashi • Moore, Joel • Perl, Nicholas Robert • Iyengar, Rajesh R. • Mermerian, Ara • Im, G-yoon Jamie • Lee, Thomas Wai-Ho • Hudson, Colleen • RENNIE, Glen Robert • Jia, Lei • Renhowe, Paul Allan • Barden, Timothy Claude • Yu, Xiang Y. • SHEPPECK, James Edward • Iyer, Karthik • Jung, Joon • MILNE, George Todd • LONG, Kimberly Kafadar • Currie, Mark G.
Assignees
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Publication Number
US-11207323-B2
Publication Date
2021-12-28
Expiration Date
Abstract
Compounds of Formulae I′ and I are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.
Core Innovation
The disclosure is directed to compounds represented by specified structural formulae and pharmaceutically acceptable salts thereof. The structures include fluorinated heteroaromatic, heterocyclic, fused polyheteroaromatic, and polycyclic scaffolds with variable substituent patterns, including carboxylic acid, ester, amide, amine, sulfonamide, sulfone, amino, cyano, hydroxyl, alkoxy, nitro, halogen, and protected amine motifs. Some embodiments are described as sGC stimulators, NO-independent and heme-dependent activators of soluble guanylate cyclase.
The material also includes broad structural definitions for compound families across multiple formula sets, with ring systems defined as heteroaryl, oxazole, isoxazole, fused heteroaromatic, and related heterocyclic motifs. The disclosure presents multiple exemplified compound series and labeled compounds as structural embodiments of the claimed chemical space, with some embodiments marked by stereochemical annotation such as Abs.
The documents further describe pharmaceutical composition embodiments in which the claimed compound or its pharmaceutically acceptable salt is combined with one or more excipients. Synthetic and transformation content is also present in the source material, alongside biological evaluation, synthesis, and characterization content.
Claims Coverage
The consolidated claim coverage is centered on compounds defined by specified structural formulae, with pharmaceutically acceptable salts included. Across the provided items, the independent claim themes repeatedly reduce to formula-defined compounds, and some items also include pharmaceutical composition coverage with excipients. In total, the recurring inventive features are structural formula-defined compounds and, where present, pharmaceutical composition embodiments.
Compound defined by structural formula
A compound represented by a specified structural formula, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition containing the compound
A pharmaceutical composition including the compound represented by the structural formula, or a pharmaceutically acceptable salt thereof, together with one or more excipients.
sGC stimulator compound
A compound represented by Formula I or Formula I′ as an sGC stimulator, including NO-independent and heme-dependent activation of soluble guanylate cyclase in the stated context.
Overall, the claims are consistently directed to structural-formula-defined compounds and pharmaceutically acceptable salts, with dependent claim families in some items adding pharmaceutical composition coverage and excipients. In the sGC-related material, the structural-formula compound is additionally characterized as an sGC stimulator.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic use as sGC stimulators for diseases and conditions where NO–cGMP signaling is beneficial.
Therapeutic use in connection with vascular disorders, pulmonary hypertension, thromboembolic disease, fibrotic disorders, ocular disorders, hearing disorders, CNS disorders, circulation, topical, skin, and metabolic disorders.
Delivery concepts using implanted or drug-eluting stents, including CABG-related indications such as saphenous graft failure, revascularization, thrombosis, restenosis, anti-remodeling, endothelialization, and anti-apoptotic effects.
Therapeutic indication contexts referenced for CFTR-related disease, neuromuscular disorders via nNOS localization, muscular dystrophy, sickle cell disease, bladder dysfunction, atherosclerosis, and wound healing.
Biological evaluation contexts including sGC-HEK cGMP assay workflow, thoracic aortic rings assay, and blood pressure studies in rats.
Therapeutic methods where the disclosed compounds are used as soluble guanylate cyclase (sGC) stimulators for disorders including cardiovascular, pulmonary, renal, hepatic, ocular, and sexual disorders.
Disorders including pulmonary hypertension, arterial hypertension, heart failure, renal fibrosis, liver cirrhosis, erectile dysfunction, and female sexual dysfunction.
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