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-9227918-B2
Publication Date
2016-01-05
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 describes short-acting pharmaceutical compositions comprising phenylalkylamine L-type calcium channel blockers defined by Formula I, including pharmaceutically acceptable addition salts, enantiomers, and diastereomers. The compounds are presented as short-acting with duration of action less than 60 minutes, preferably about 1 to 30 minutes, and with rapid onset followed by rapid inactivation or effect before metabolic inactivation.
The disclosed subject matter provides a short-acting pharmaceutical composition comprising a compound having a specific structural formula, or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof. The structure includes substituent variables and independently defined substituent options, with at least one specified group being CO2R10, or lower alkyl or lower alkoxyalkyl substituted with CO2(lower alkyl) or CO2(lower alkoxyalkyl).
The document also includes oxalate salt forms and hydrochloride derivatives, including verapamil-oxalate and verapamil-HCl, with multiple stereochemical variants. The text further describes rapid treatment in ischemic heart conditions and multiple cardiovascular emergencies, and broad pharmaceutical composition aspects including buccal, sublingual, transdermal, topical, intranasal, inhalation, and parenteral administration such as intravenous administration.
Claims Coverage
The consolidated claim coverage includes independent claims directed to short-acting pharmaceutical compositions defined by a specific structural formula or by selection from a specified group of compounds. The inventive features center on the Formula I framework, permitted salts and stereoisomers, the short-acting effect before metabolic inactivation, and therapeutic indication language for ischemic heart conditions and cardiac arrhythmia.
Short-acting pharmaceutical composition defined by a specific structural formula with pharmaceutically acceptable salts and stereoisomers
A short-acting pharmaceutical composition comprising a compound having a defined structural formula, or a pharmaceutically acceptable addition salt thereof, or any enantiomer or diastereomer thereof, with independently selectable linkages and substituent groups as recited, and with at least one specified group selected to be CO2R10 or lower alkyl/lower alkoxyalkyl substituted with —CO2(lower alkyl) or —CO2(lower alkoxyalkyl).
Time-to-effect prior to metabolic inactivation
The short-acting pharmaceutical composition wherein the compound produces the desired effect within 1 to 30 minutes before being metabolically inactivated.
Pharmaceutical composition comprising a compound selected from a specified group
A pharmaceutical composition comprising a compound selected from the group consisting of the specified compounds, including depicted group members and specific depicted structures.
Treatment of ischemic heart conditions and cardiac arrhythmia
A pharmaceutical composition formulated to treat ischemic heart conditions and cardiac arrhythmia.
The claims center on a short-acting pharmaceutical composition defined by a specific structural formula or by selection from a specified group of compounds, with permitted salts and stereoisomers. The scope is further limited by a desired effect window before metabolic inactivation and by therapeutic indications for ischemic heart conditions and cardiac arrhythmia.
Stated Advantages
Short-acting duration of action less than 60 minutes, preferably about 1 to 30 minutes.
Rapid onset followed by rapid inactivation.
Short-acting behavior before metabolic inactivation.
Desired therapeutic effect within 1 to 30 minutes.
Documented Applications
Treatment of ischemic heart conditions including stable, unstable, and vasospastic (Prinzmetal) angina.
Treatment of cardiac arrhythmias including atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
Treatment of hypertensive crisis and perioperative hypertension.
Treatment of no-reflow phenomenon after reperfusion.
Treatment of disorders linked to decreased skeletal muscle blood flow, including Raynaud’s phenomenon and intermittent claudication.
Broad pharmaceutical administration by buccal, sublingual, transdermal, topical, intranasal, inhalation, and parenteral routes including intravenous administration.
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