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-10639308-B2
Publication Date
2020-05-05
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 soluble guanylate cyclase (sGC) stimulator compounds that increase cyclic GMP (cGMP) through heme-dependent, nitric oxide (NO)-independent sGC activation. The disclosure emphasizes sGC activation as a pharmacologic mechanism that does not rely on nitric oxide. The compounds are described in terms of compounds of Formula I and compounds of Formula I', including broad structural definitions for variable substituents and ring systems.
The disclosure defines variable chemical features using parameters for X and ring A/B/C/D, together with linkers and J/JB/JA/JD, and provides definitional language for chemical terms such as isotopes and different ring types. The structural description includes language about excluded depicted compound(s) and supports variations through optional substitution behavior for defined positions. Pharmaceutical compositions and dosage forms are also described for these sGC stimulator compounds and salts.
Methods are described for treating or preventing diseases and conditions responsive to sGC stimulation, encompassing vascular/endothelial disorders, pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, and renal/hepatic disorders including renal fibrosis and failure and liver cirrhosis. Additional treated conditions include lung fibrosis, ocular/CNS disorders, urogenital/sexual disorders, wound-healing disorders, and lipid/metabolic disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis. Independent claim coverage in the provided claims specifically includes treatment of diabetic nephropathy by administering a therapeutically effective amount of compound 1-324 or a pharmaceutically acceptable salt thereof.
Claims Coverage
The independent claim provided is directed to a method of treating diabetic nephropathy by administering a therapeutically effective amount of compound 1-324 or a pharmaceutically acceptable salt. The claim set further supports dependent refinements by adding one or more additional therapeutic agents, including enumerated drug classes and specific named agents.
Treating diabetic nephropathy with compound 1-324
A method of treating diabetic nephropathy in a subject in need of treatment, comprising administering a therapeutically effective amount of compound 1-324 or a pharmaceutically acceptable salt thereof to the subject in need of treatment.
Adding one or more additional therapeutic agents
The method further provides that the treatment includes one or more additional therapeutic agents selected from listed cardiovascular and metabolic drug classes, with further selections among named agents and subclasses as specified in the dependent claims.
Selecting SGLT-2 inhibitors and specified combinations
The one or more additional therapeutic agents are SGLT-2 inhibitors selected from dapagliflozin, tofoglifozin (CSG-452), canagliflozin, canagliflozin combined with metformin hydrochloride, dapagliflozin combined with metformin hydrochloride, empagliflozin, empagliflozin combined with linagliptin, luseoglifozin, and ipragliflozin L-proline.
Selecting ACE inhibitors and specified examples
The angiotensin converting enzyme (ACE) inhibitors are selected from sulfhydryl-containing agents, dicarboxylate-containing agents, phosphonate-containing agents, naturally occurring ACE inhibitors, and include alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, and spirapril.
Selecting calcium channel blockers within specified subclasses
The calcium channel blockers are selected from specified dihydropyridine, phenylalkylamine, benzothiazepine, and nonselective calcium channel inhibitor drugs, including amlodipine, verapamil, and other named examples listed across these subclasses.
Including sacubitril and valsartan as an additional therapy
The additional therapeutic agents comprise a combination of sacubitril and valsartan.
Across the provided claims, the core claim focuses on treating diabetic nephropathy with compound 1-324 (or a pharmaceutically acceptable salt). Dependent coverage narrows or expands the treatment by specifying one or more additional therapeutic agents, including enumerated diabetes drugs such as SGLT-2 inhibitors and their named combinations, cardiovascular classes such as ACE inhibitors and calcium channel blockers with named examples, and an explicit sacubitril/valsartan combination.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating diabetic nephropathy by administering compound 1-324 or a pharmaceutically acceptable salt thereof.
Treating or preventing diseases and conditions responsive to sGC stimulation, including vascular/endothelial disorders, pulmonary hypertension, arterial hypertension, heart failure, atherosclerosis, inflammation, thrombosis, renal fibrosis and failure, liver cirrhosis, lung fibrosis, ocular/CNS disorders, urogenital/sexual disorders, wound-healing disorders, and lipid/metabolic disorders such as dyslipidemia, hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liver disease, and hepatitis.
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