Metalloenzyme inhibitor compounds
Inventors
Sparks, Steven • Yates, Christopher M. • Shaver, Sammy R.
Assignees
Corxel Pharmaceuticals Hong Kong Ltd • Mycovia Pharmaceuticals Inc
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Publication Number
US-11136309-B2
Publication Date
2021-10-05
Expiration Date
Abstract
Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Core Innovation
The invention relates to a method of reducing one or more symptoms of an aldosterone related disease or disorder in a subject suffering from the disease or disorder by administering to the subject in need thereof an effective amount of a compound of a specified formula, or a pharmaceutically acceptable salt thereof. The compound structure is defined by substituent variables A, W, X, Y, and Z, together with R1, R2, R3, R4, R6, Ra, Rb, Rc, Rd, Re, Rf, and an index n, with extensive permitted groups including halogen, cyano, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, haloalkyl, and ring-forming combinations.
The patent further frames the covered disease states through dependent claim refinements that identify mediation by aldosterone synthase (CYP11B2) or 11-beta-hydroxylase (CYP11B1). Additional refinements limit the covered aldosterone related disease or disorder to cardiovascular, endocrinologic, inflammatory, gynecologic, urologic, or gastrointestinal disease categories, and further to hypertension-related conditions and an extensive enumeration of specific cardiovascular, renal, metabolic, hepatic, vascular, and neurological diseases and conditions.
The provided examples present substituted benzimidazole and pyrimidine derivatives associated with the aldosterone-related compound scaffold context, with characterization reported by LC-MS, 1H NMR, and HPLC. The examples include imidazo[4,5-b]pyridine and benzo[d]imidazole derivatives bearing substituents such as difluoromethyl, difluoroethyl, trifluoromethyl, nitrile, chloro, fluoro, methoxy, methylsulfonyl, and carboxamide or related carbonitrile features, together with reported yields and purity metrics.
Claims Coverage
The claim set contains one independent claim, directed to reducing one or more symptoms of an aldosterone related disease or disorder by administering an effective amount of a compound defined by a detailed multi-ring/substituent formula (or a pharmaceutically acceptable salt). Dependent claims refine the disease mediation target and narrow the covered disease and condition scope.
Administering a formula-defined compound to reduce aldosterone symptoms
A method of reducing one or more symptoms of an aldosterone related disease or disorder in a subject, comprising administering an effective amount of a compound of the formula (or a pharmaceutically acceptable salt), wherein A is N; W, X, Y, and Z are CR6; and the substituent definitions for R1, R2, R3, R4, R6, Ra, Rb, Rc, Rd, Re, Rf, and n are specified by the claim.
Aldosterone disease mediated by CYP11B2 or CYP11B1
The method wherein the aldosterone related disease or disorder is mediated by aldosterone synthase (CYP11B2) or 11-beta-hydroxylase (CYP11B1).
Aldosterone disease limited to selected disease categories
The method wherein the aldosterone related disease or disorder is limited to cardiovascular, endocrinologic, inflammatory, gynecologic, urologic, or gastrointestinal disease categories.
Aldosterone disease including hypertension-related and enumerated conditions
The method wherein the aldosterone related disease or disorder includes hypertension-related conditions and an enumerated list of specific cardiovascular, renal, metabolic, hepatic, vascular, and neurological diseases and conditions.
Overall, claim coverage centers on administering an effective amount of a compound of the specified multi-variable formula (or a pharmaceutically acceptable salt) to reduce one or more symptoms of an aldosterone related disease or disorder. Dependent claims refine the method by specifying CYP11B2 or CYP11B1 mediation, narrowing disease categories, and further restricting the scope to hypertension-related conditions and an enumerated list of aldosterone-related disease states.
Stated Advantages
Selective inhibition of aldosterone synthase (CYP11B2) is described relative to the concern of non-selective CYP11B2 inhibition and associated cortisol suppression concerns.
Reducing one or more symptoms of an aldosterone related disease or disorder in a subject suffering from said disease or disorder.
Provides intermediate characterization data using 1H NMR and LC-MS purity/m/z outcomes.
Supports the availability of a series of cyclopropyl-substituted aromatic/heteroaromatic intermediates and subsequent functionalization stages.
Documented Applications
Reducing one or more symptoms of an aldosterone related disease or disorder in a subject by administering an effective amount of a compound of the specified formula or Formula I, or a pharmaceutically acceptable salt.
Treatment scope is described for aldosterone-related disease indications including hypertension, resistant hypertension, and conditions associated with primary or secondary hyperaldosteronism and adrenal hyperplasia.
The disclosed indications include pulmonary arterial hypertension, heart failure, hypokalemia, renal failure and chronic renal failure, fibrosis and collagen formation, atrial fibrillation, sleep apnea or obstructive sleep apnea, diabetic nephropathy and glomerulosclerosis, stroke, and other enumerated cardiovascular, renal, metabolic, hepatic, vascular, and neurological diseases.
Synthesis and characterization of aldosterone-pathway-related heteroaryl and cyclopropyl-containing compounds, including preparation of pyridinyl pyrimidine carboxamides and ring-forming transformations to imidazo[4,5-b]pyridines bearing difluoromethyl, difluoroethyl, trifluoromethyl, and nitrile substituents.
Synthetic examples describe preparing and characterizing aldosterone-disorder-relevant benzimidazole/pyrimidine derivatives and related fluorinated or cyano-substituted variants, with analytical characterization reported by LC-MS, HPLC purity, and 1H NMR.
CYP11B2 and CYP11B1 metalloenzyme inhibitor testing using LC-MS readouts of aldosterone and cortisol, including IC50 calculation methodology and CYP11B2 activity table entries with compound IDs, structures, and IC50 values.
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