sGC stimulators
Inventors
Nakai, Takashi • 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. • Moore, Joel • Perl, Nicholas Robert • Iyengar, Rajesh R. • Mermerian, Ara • Im, G-yoon Jamie • Lee, Thomas Wai-Ho • Hudson, Colleen • RENNIE, Glen Robert
Assignees
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Publication Number
US-10183021-B2
Publication Date
2019-01-22
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 provides soluble guanylate cyclase (sGC) stimulators that act as NO-independent, heme-dependent sGC activators. The compounds are defined by Formula I′ and Formula I, including broad substitution-variable definitions for the core chemotypes, together with specified exclusions of certain depicted compounds.
The document describes compositions and derivatives that include fluorinated (3,3,3-trifluoropropyl)hydrazine and downstream pyrazole and isoxazole derivatives, with examples including ethyl 3-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylate and 5-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboximidamide. It also describes multiple named compounds such as Compound I-507, I-511, I-513, I-516, I-517, I-523, I-573, I-588, I-617, I-618, I-619, I-620, I-621, I-623, I-479, I-595, and chiral I-530/I-531.
The disclosure further provides definitions for substitution variables and structural interpretation for multiple ring and substituent patterns within the Formula I′/Formula I scaffold. It also includes pharmaceutical compositions comprising the compounds and describes therapeutic and preventive disease treatment use in connection with sGC stimulation.
The disclosed use ties the described compounds to treating resistant hypertension in subjects in need of treatment. The independent claim method uses compound I-324 or a pharmaceutically acceptable salt as a therapeutic agent in a subject with resistant hypertension while the subject is on concurrent use of at least three antihypertensive agents belonging to different antihypertensive drug classes.
Claims Coverage
The consolidated claim coverage centers on treating resistant hypertension by administering compound I-324 or a pharmaceutically acceptable salt to a subject concurrently using at least three antihypertensive agents from different classes. Other disclosed claim content covers Formula I′/Formula I sGC stimulators, but no independent claim is explicitly described for that disclosure in the provided inputs.
Treating resistant hypertension with compound I-324 during concurrent multi-class antihypertensive use
A method of treating resistant hypertension in a subject in need of treatment by administering a therapeutically effective amount of compound I-324 or a pharmaceutically acceptable salt thereof, wherein the subject is on concurrent use of at least three antihypertensive agents belonging to different antihypertensive drug classes selected from angiotensin-converting-enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), calcium channel blocker, diuretic, and beta blocker.
NO-independent, heme-dependent sGC activators
Compounds defined by Formula I′ and Formula I as soluble guanylate cyclase stimulators that act as NO-independent, heme-dependent sGC activators, with broad substitution-variable definitions and specified exclusions of certain depicted compounds.
The claims collectively focus on compound I-324 for resistant hypertension with concurrent multi-class antihypertensive therapy, and on Formula I′/Formula I sGC stimulators defined as NO-independent, heme-dependent activators.
Stated Advantages
Acts as an NO-independent, heme-dependent sGC activator that supports conversion of GTP to cyclic GMP (cGMP) via sGC.
Addresses disorders associated with reduced NO bioavailability and reduced NO responsiveness by providing NO-independent sGC stimulation and direct cGMP production.
Stated differentiating features include reduced heme dependency, synergistic activation with NO, and direct cGMP production.
Documented Applications
Treating resistant hypertension in a subject in need of treatment.
Therapeutic and preventive treatment of cardiovascular and related disorders described as including pulmonary hypertension, systemic hypertension, heart failure, and atherosclerosis.
Therapeutic and preventive treatment of pulmonary, renal, hepatic, thromboembolic, and fibrotic disorders as described in the disclosure.
Therapeutic and preventive treatment of ocular, hearing, and CNS disorders as described in the disclosure.
Therapeutic and preventive treatment of sexual disorders described as including erectile dysfunction, female sexual arousal disorder, and vaginal atrophy.
Therapeutic and preventive treatment of lipid-related disorders described as including dyslipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver disease, and hepatitis.
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