Short acting phenylalkylamine calcium channel blockers and uses thereof

a technology of phenylalkylamine and calcium channel blocker, which is applied in the field of short-acting phenylalkylamine calcium channel blocker, can solve the problems of insufficient blood oxygen supply, permanent damage to the heart, and irregular heartbea

Inactive Publication Date: 2010-07-29
MILESTONE PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]Given the prevalence of cardiovascular disorders in patients, there is a need for new and improved compound and methods for treating cardiovascular disorders including ischemic heart conditions and cardiac arrhythmias.

Problems solved by technology

Angina is a symptom of insufficient blood oxygen supply to an area of the heart due to an imbalance of the oxygen supply-demand ratio.
Angina is usually precipitated following exertion or emotional stress in susceptible patients due to an inability of the coronary vasculature to provide sufficient cardiac oxygen perfusion.
Sustained reduced blood flow (ischemia) to the heart can cause permanent damage to the heart due to the death of cardiac muscle.
In atrial fibrillation, the electrical discharges are rapid and irregular, resulting in an irregular rhythm of heart contraction.
These rapid and irregular discharges result in rapid and ineffectual atrial contractions that reduce the ability of the atria to supply blood to the ventricles.

Method used

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  • Short acting phenylalkylamine calcium channel blockers and uses thereof
  • Short acting phenylalkylamine calcium channel blockers and uses thereof
  • Short acting phenylalkylamine calcium channel blockers and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

5-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile (1f)

[0321]Method A Step 1: To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrile in 141 mL of tetrahydrofuran (THF) at −30° C., was slowly added 56.4 mL (56.4 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 10.6 mL (113.0 mmol) of 2-bromopropane was added. The mixture was heated to reflux for 2 hours (h) then left at 22° C. for about 16 h. A saturated aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate / hexane to give 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil.

[0322]Method A Step 2: To a solution of 11.21 g (51.1 mmol) of 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile in 126 ...

example 2

1a: Dimethyl 2-(3-bromopropyl)-2-(3,4-dimethoxyphenyl)malonate

[0324]For Step 1, (3,4-dimethoxy-phenyl)-acetic acid methyl ester was substituted for (3,4-Dimethoxyphenyl)acetonitrile, dimethyl carbonate was substituted for 2-bromopropane and sodium hydride was substituted for NaHMDS. For Step 2, sodium hydride was substituted for NaHMDS.

example 3

1b: Methyl 5-bromo-2-cyano-2-(3,4-dimethoxyphenyl)pentanoate

[0325]For Step 1, dimethyl carbonate was substituted for 2-bromopropane and sodium hydride was substituted for NaHMDS.

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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.

Description

BACKGROUND OF THE INVENTION[0001]The invention relates to the use of phenylalkylamine compounds which block L-type calcium channels to treat cardiovascular disorders.Calcium Channel Blockers[0002]Calcium channel blockers (CCBs) are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias and include a heterogeneous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels. Calcium influx through these channels initiates a process of electromechanical coupling that ultimately leads to muscle contraction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a powerful therapeutic approach to the treatment of angina and hypertension, respectively. Likewise, blocking calcium influx into cardiac tissues and conduction systems provides a useful a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/277C07C217/62A61K31/216C07C255/43A61P9/12A61P9/06A61P9/10
CPCC07C255/43A61K31/275C07C229/38C07C255/42C07C229/34A61K31/277A61K31/216A61K31/26A61P21/00A61P43/00A61P9/00A61P9/06A61P9/10A61P9/12
Inventor MAGUIRE, MARTIN P.RIOUX, ELISELEIGHTON, HARRY J.
Owner MILESTONE PHARMA INC
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