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-9481689-B2
Publication Date
2016-11-01
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 formula-defined chemical compounds, including pharmaceutically acceptable salts thereof, within fluorinated heteroaromatic and heterocyclic scaffold families. The described structures include nitrogen-rich fused heteroaromatic cores, heteroaromatic or heterocycle ring systems, and variability in substituent patterns such as fluorine, halogen, carboxylic acid, ester, amide, sulfonamide, sulfone, hydroxyl, heteroaryl, alkyl, amino, cyano, and trifluoromethyl groups. The examples are presented as compound series and structural embodiments rather than as process details.
In one part of the disclosure, the patent discloses sGC-stimulator compounds corresponding to Formula I and Formula I′, with pharmaceutically acceptable salts, NO-independent stimulation with reduced prosthetic heme dependency, and synergistic activation with NO. The document also includes synthetic preparation, characterization, and related intermediates for multiple members of the compound family, including named compounds and example series such as I-248, I-250, I-252, I-253, I-260, I-262, I-265, I-267, I-269, I-278 through I-302, I-354 through I-379, I-392 through I-416, I-430 through I-455, I-449 through I-474, I-506 through I-531, I-563 through I-588, and others.
The disclosure further presents additional compound families including fluorinated oxadiazole-based amine intermediates and related analogs, as well as (3,3,3-trifluoropropyl) hydrazine/pyrazole series, including named intermediates and compounds such as (3,3,3-trifluoropropyl)hydrazine hydrochloride, ethyl 3-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylate, 5-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboximidamide, and compounds I-507, I-511, I-513, I-516/I-517, I-523, I-588, I-617/I-618/I-619/I-620/I-621, I-623, and I-626. Across these series, the compounds are characterized by formula-based structural definitions with diverse fused ring systems, stereochemical variants, and functional-group substitutions.
Claims Coverage
The consolidated claim coverage centers on formula-defined compounds, or pharmaceutically acceptable salts thereof, with dependent coverage that adds pharmaceutical composition formulations comprising one or more excipients. Across the input items, the claims repeatedly identify one principal compound-level inventive concept and one composition-level refinement, for a total of two recurring claim-level features.
Formula-defined compound or pharmaceutically acceptable salt
A compound of formula, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with excipients
A pharmaceutical composition comprising the compound of formula, or a pharmaceutically acceptable salt thereof, and one or more excipients, using comprising/open-ended composition language.
Overall, the claims are directed to formula-defined compound families, including pharmaceutically acceptable salts, and to pharmaceutical compositions containing the claimed compound or salt together with one or more excipients.
Stated Advantages
Sustains sGC stimulation as NO-independent with reduced prosthetic heme dependency.
Provides synergistic activation with NO.
Produces downstream cGMP-mediated effects.
Documented Applications
Cardiovascular/pulmonary hypertension conditions where NO or cGMP increases are beneficial.
Fibrotic disorders where NO or cGMP increases are beneficial.
Renal disorders where NO or cGMP increases are beneficial.
Hepatic disorders where NO or cGMP increases are beneficial.
Erectile dysfunction/sexual disorders where NO or cGMP increases are beneficial.
Lipid-related disorders where NO or cGMP increases are beneficial.
Whole-cell soluble guanylate cyclase (sGC) activation assays, including measurement of cGMP generation in HEK293 cells with LC/MS detection and HTRF (cGMP HTRF assay), and EC50/Emax reporting for sGC stimulation.
Blood pressure change in rats is mentioned as part of Example 4.
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