Short acting phenylalkylamine calcium channel blockers and uses thereof
Inventors
Maguire, Martin P. • Rioux, Elise • Leighton, Harry J.
Assignees
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Publication Number
US-9463179-B2
Publication Date
2016-10-11
Expiration Date
Abstract
The present invention relates to the use of a pharmaceutically effective amount of an short-acting calcium channel blocking compound to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension before, during, or after surgery, no-reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.
Core Innovation
The invention relates to phenylalkylamine or verapamil compound selection with pharmaceutically acceptable addition salts, enantiomers or diastereomers, and is positioned around short duration behavior and esterase-sensitive inactivation in serum. The document also describes multiple small-molecule compounds and their salt forms, including verapamil-HCl and a series of verapamil oxalates, together with exemplified compounds and related chemical structure depictions.
The disclosed compounds include structural features such as bromo or chloro substituents, cyano groups, malonate or dicarboxylate motifs, benzoate or isophthalate motifs, methoxy or dimethoxy aryl substituents, and an amine side chain including methylamino. The description further includes oxalate salt forms, parent cation structures with a dimethyl or aryl ring system and tertiary amine linkage, and related HCl salt forms of certain enantiomeric or mixture forms.
The content also includes calcium-channel binding inhibition constants and references rat brain membrane radioligand binding using [3H]-Desmethoxyverapamil, with Ki values calculated using the Cheng-Prusoff relationship. It further describes topical pharmaceutical formulation and delivery aspects with antioxidants, preservatives, chelating agents, neutralizing agents for pH adjustment, hydrophilic gelling agents, solvents, skin penetration enhancers, hyaluronic acid and its salt forms, topical administration regimens, and carriers or technologies including liposomes, microsomes, microsponges, and patches.
Claims Coverage
The independent claims provide coverage for method treatment of an ischemic heart condition or cardiac arrhythmia by administering a therapeutically effective amount of a phenylalkylamine or verapamil compound, either defined by a specified structural formula and substituent constraints or selected from a depicted group. Across the claim set, the inventive features total at least two independent frameworks: formula-defined compound administration and depicted-group compound administration.
Formula I compound administration for ischemic heart conditions and cardiac arrhythmias
Administering to a patient in need a therapeutically effective amount of a compound having the formula and substituent constraints, including a pharmaceutically acceptable addition salt and any enantiomer or diastereomer.
Depicted-group compound administration for ischemic heart conditions and cardiac arrhythmias
Administering to a patient in need a therapeutically effective amount of a compound selected from the group consisting of the depicted compounds, or a pharmaceutically acceptable addition salt thereof, for treating an ischemic heart condition or cardiac arrhythmia.
Selection of compound from depicted group
Using a compound selected from the set of compounds shown in the claim images, including pharmaceutically acceptable addition salts thereof.
Formula-defined compound with stereochemical and substituent constraints
A therapeutically effective amount of a compound having a specific formula with selections for a–f and constraints on R11–R17, R10, R18, and g/R19/R20, or a pharmaceutically acceptable addition salt, or any enantiomer or diastereomer thereof.
Ischemic heart condition subtype limitation to angina variants
The ischemic heart condition is one of stable angina, unstable angina, or vasospastic angina.
Cardiac arrhythmia subtype limitation to enumerated rhythm disorders
The cardiac arrhythmia is selected from atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes.
The claim coverage is centered on method treatment of ischemic heart conditions and cardiac arrhythmias using a therapeutically effective amount of a compound from a defined phenylalkylamine or verapamil compound set, including salt and stereochemical variants. Dependent claims further narrow ischemic conditions to stable angina, unstable angina, or vasospastic angina, and narrow arrhythmias to an enumerated set including atrial fibrillation, atrial flutter, PSVT, premature atrial, nodal, or ventricular depolarizations, atrial tachycardia, ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
Stated Advantages
Rapid inactivation behavior while providing treatment across the enumerated cardiovascular conditions.
A qualitative in-vitro plasma stability ranking approach is discussed with respect to ester-hydrolysis sensitivity.
Documented Applications
Treatment of ischemic heart conditions.
Treatment of cardiac arrhythmias.
Topical administration.
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