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, James • 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-9586937-B2
Publication Date
2017-03-07
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 invention relates to compounds defined by specified formulas, including pharmaceutically acceptable salts thereof. The disclosed subject matter repeatedly presents fluorinated, nitrogen-rich heteroaromatic or fused heteroaromatic scaffolds with variable substituents, aryl linkers, ring systems, and side-chain functional groups. The examples and structural depictions illustrate broad formula-based chemical scope across multiple compound series.
The disclosed embodiments include heteroaromatic cores with O-N heterocycle characteristics, fused bicyclic or benzene-fused frameworks, and substituted sulfonamide, sulfonyl, amide, carboxylic acid, ester, amino, hydroxyl, and cyclic substituent patterns. Several series show fluorine substitution, stereochemical variation, and alternative ring or linker configurations while maintaining the same general compound family. The disclosure also includes pharmaceutically acceptable salt forms and, in some portions, pharmaceutical composition context with excipients.
A further part of the disclosure relates to soluble guanylate cyclase (sGC) stimulator compounds that are heme-dependent and described in the context of nitric oxide-independent sGC stimulation. These compounds are stated to stimulate sGC and increase NO/cGMP, and the text associates them with a broad therapeutic scope and combination therapy concepts. The overall core innovation is the provision of formula-defined compound families and related compositions within the stated structural and therapeutic frameworks.
Claims Coverage
The provided claims are centered on formula-defined compounds, with pharmaceutically acceptable salts explicitly included, and dependent claims commonly adding a pharmaceutical composition context through excipients. Across the consolidated inputs, the inventive features are broad formula coverage and, where present, formulation of the claimed compound with excipients.
Compound of specified formula or pharmaceutically acceptable salt
A compound defined by a specified formula, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including the claimed compound and excipients
A pharmaceutical composition that includes the compound of the formula (or its pharmaceutically acceptable salt) together with one or more excipients.
Overall, the claim coverage is broad at the compound-definition level and is narrowed in dependent claims by adding a pharmaceutical composition requirement involving excipients. In the portions that address sGC stimulators, the coverage is likewise anchored to formula-defined compounds and their pharmaceutically acceptable salts.
Stated Advantages
Stimulating soluble guanylate cyclase (sGC) to increase NO/cGMP.
NO-independent sGC stimulation that is heme-dependent.
Treatment and prevention of a wide range of disorders associated with altered NO/cGMP signaling.
Documented Applications
Treatment and prevention of pulmonary hypertension and arterial hypertension.
Treatment and prevention of heart failure.
Treatment and prevention of atherosclerosis, thromboembolic disease, and ischemic diseases.
Treatment and prevention of renal and hepatic disorders, including fibrosis and cirrhosis.
Treatment and prevention of erectile dysfunction and female sexual dysfunction.
Treatment of ocular disorders, hearing disorders, skin disorders, and wound healing.
Treatment of cardiovascular, respiratory, renal, hepatic, ocular, CNS, circulation-related, urogenital, sexual, lipid-related, and fibrosis disorders.
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