Compounds and compositions comprising the same for treating hypertension or heart failure
Inventors
Balavoine, Fabrice • Compere, Delphine • KECK, MATHILDE • Marc, Yannick • Llorens-Cortes, Catherine • BOITARD, SOLÈNE E.
Assignees
Centre National de la Recherche Scientifique CNRS • Institut National de la Sante et de la Recherche Medicale INSERM • Quantum Genomics SA • College de France
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Publication Number
US-11345658-B2
Publication Date
2022-05-31
Expiration Date
Abstract
The present invention relates to compounds, to compositions comprising the same, to methods for preparing the compounds, and the use of these compounds in therapy. In particular, the present invention relates to a compound that is useful in the treatment and prevention of primary and secondary arterial hypertension, ictus, myocardial ischaemia, cardiac and renal insufficiency, myocardial infarction, peripheral vascular disease, diabetic proteinuria, Syndrome X and glaucoma.
Core Innovation
The document describes therapeutic class brain aminopeptidase A (APA) inhibitors for treating and/or preventing primary and secondary arterial hypertension and related cardiovascular, renal, and neurologic diseases. The background problem focuses on arterial hypertension and associated conditions, as well as end-organ consequences such as heart failure, myocardial ischemia, myocardial infarction, cardiac and renal insufficiency, stroke (ictus), and other listed vascular, renal, neurologic, and ocular disorders.
The core invention provides a compound scaffold defined by formulas (I) and (II), including the permitted acidic group AH as −CO2H, −SO3H, or −PO3H2, and the index m being 1, 2, or 3. The scaffold further defines substituents R1 and R2 as independently H, a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group, where each group is optionally substituted by selected aryl, heterocycle, cycloalkyl, O-aryl, O-arylalkyl, or O-cycloalkyl groups, which themselves may be optionally substituted with selected radicals.
The compounds are provided in pharmaceutical forms including pharmaceutical salts, solvates, zwitterionic forms, and any prodrug thereof. The document also discloses pharmaceutical compositions comprising the inhibitor compounds and medical uses defined as methods of prevention and treatment of arterial hypertension and related diseases, including manufacture of a medicament for such prevention and treatment.
Claims Coverage
The independent claims include five inventive features centered on the defined inhibitor compound scaffold, its pharmaceutical forms, the composition, and therapeutic use for arterial hypertension and related diseases.
Defined compound scaffold with AH and substituent R1/R2 in formulas (I) and (II)
A compound having formula (I) or formula (II), wherein AH represents −CO2H, −SO3H, or −PO3H2; m is 1, 2 or 3; and R1 and R2 independently represent H or a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted by selected aryl/heterocycle/cycloalkyl/O-aryl/O-arylalkyl/O-cycloalkyl groups, each of which may be optionally substituted with selected radicals.
Pharmaceutical salt, solvate, zwitterionic form or prodrug of the defined compound
The compound of formulas (I) or (II) is provided as a pharmaceutical salt, solvate, zwitterionic form, or any prodrug thereof.
Prevention or treatment of arterial hypertension and related diseases by administering a therapeutically effective amount
A method of preventing or treating arterial hypertension and related diseases by administering to a subject in need a therapeutically effective amount of a compound according to the defined formula (I) or (II) scaffold.
Pharmaceutical composition comprising at least one defined compound and pharmaceutically acceptable carrier
A pharmaceutical composition comprising at least one compound according to the defined formula (I) or (II) scaffold together with a pharmaceutically acceptable carrier.
Targeting an enumerated set of arterial-hypertension-related diseases
The prevention or treatment method covers diseases directly or indirectly related to arterial hypertension from a group including heart disease, heart failure, stroke, peripheral and/or cerebral vascular system diseases, and brain, eye, and/or kidney diseases.
Overall claim coverage is anchored by the defined brain aminopeptidase A inhibitor compound scaffold in formulas (I) and (II) with constrained AH, m, and R1/R2 substitution patterns, extended to pharmaceutical salt/solvate/zwitterionic/prodrug forms, and linked to methods of preventing or treating arterial hypertension and specified related diseases, as well as to pharmaceutical compositions containing the defined compounds with a pharmaceutically acceptable carrier.
Stated Advantages
Treating and/or preventing primary and secondary arterial hypertension.
Treating and/or preventing related cardiovascular, renal, and neurologic diseases.
Improving functional outcomes in a post-myocardial infarction context via increased left ventricular ejection fraction versus vehicle.
Documented Applications
Medical use as methods of prevention and/or treatment of primary and secondary arterial hypertension and related diseases, and manufacture of a medicament for such prevention and treatment.
Nonclinical evaluation of brain APA inhibition and associated blood pressure/heart rate effects in hypertensive models, and functional improvement after myocardial infarction (left ventricular ejection fraction) versus vehicle.
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