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-10010524-B2
Publication Date
2018-07-03
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 concerns short-acting phenylalkylamine (L-type) calcium channel blocker compounds that include esterase-sensitive groups and are discussed in connection with serum esterase-mediated inactivation to provide short duration of action. The disclosed chemistry is framed within broad Formula I structural definitions and associated variable definitions, including allowed substituents and ring/linkage options.
The invention further provides chemical structure depictions and corresponding nomenclature for exemplary compounds, including Table 1 compounds (1a–1u), Table 2 compounds (2a–2o), and Table 3 compounds exemplified by a Formula 1. These exemplified structures include brominated and chlorinated cyano malonates, pentanoates, benzoates, phenoxyacetate, isophthalate motifs, and dimethoxy/nitrile/cyanovinyl-like and malonate/ester functionalities with appended tertiary/secondary amine motifs.
The patent also describes multiple salt forms and related structures, including verapamil-HCl, verapamil-oxalate variants, and numerous oxalate salts such as 3t-oxalate through 3as-oxalate. The disclosed structures share an identical core scaffold with varying substituent patterns and are presented together with structure files and nomenclature.
Claims Coverage
The provided independent claims cover emergency-room treatment of hypertensive crisis by administering a therapeutically effective amount of a compound defined by formula or selected from a stated group, including pharmaceutically acceptable addition salts and enantiomers; one claim also allows diastereomers. Across the independent claims, three inventive features appear: emergency-room hypertensive crisis treatment, formula-based compound definition, and selection from a stated compound group.
Emergency-room hypertensive crisis treatment administration
A method of treating a hypertensive crisis in an emergency room setting comprising administering to a patient in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable addition salt or enantiomer thereof.
Formula-defined phenylalkylamine calcium channel blocker compound
Administering a therapeutically effective amount of a compound having the specified formula, with each a, b, c, d, e, and f independently being —CH2—, —O—, —S—, or a single bond and with specified R-group constraints, including at least one of R11–R17 being CO2R10-type or related CO2-substituted lower alkyl or lower alkoxyalkyl groups.
Selected group of compounds including salts or enantiomers
Administering to a patient in need thereof a therapeutically effective amount of a compound selected from a stated group of compounds, or a pharmaceutically acceptable addition salt or enantiomer thereof.
The independent claims cover administering therapeutically effective amounts in an emergency room setting for hypertensive crisis, where the administered compound is either defined by the specified formula constraints or selected from a stated group, and may be provided as a pharmaceutically acceptable addition salt or an enantiomer; one claim also includes diastereomers.
Stated Advantages
Comparable results for corresponding HCl salts for certain stereochemical variants (as stated in the disclosure).
Short duration of action through serum esterase-mediated inactivation.
Documented Applications
Treating a hypertensive crisis in an emergency room setting by administering a therapeutically effective amount of the disclosed compounds (and pharmaceutically acceptable addition salts/enantiomers as recited).
Treating hypertensive crisis in an emergency room setting.
Treating ischemic heart conditions, including angina (stable, vasospastic, and unstable).
Treating cardiac arrhythmias including atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia (PSVT).
Treating perioperative or other hypertension, including hypertension before, during, or after surgery.
Treating no-reflow after reperfusion.
Treating diseases linked to decreased skeletal muscle blood flow, including Raynaud’s phenomenon and intermittent claudication.
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