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Ion channel modulating compounds and uses thereof

Inactive Publication Date: 2005-01-27
CORREVIO INT SARL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

In another embodiment, the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents under conditions where an “arrhythmogenic substrate” is present in the heart. An “arrhythmogenic substrate” is characterized by a reduction in cardiac action potential duration and / or changes in action potential morphology, premature action potentials, high heart rates and may also include increased variability in the time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes such as these are observed during conditions of myocardial ischaemia or inflammation and those conditions that precede the onset of arrhythmias such as atrial fibrillation.
In another embodiment, the present invention provides a pharmaceutical composition containing an amount of a compound of formula (I) effective to produce local analgesia or anesthesia in a warm-blooded animal in need thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The invention further provides a method for producing, local analgesia or anesthesia in a warm-blooded animal which includes administering to a warm-blooded animal in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition containing a compound of formula (I). These compositions and methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal.

Problems solved by technology

At present, there is no satisfactory pharmacotherapy for the treatment and / or prevention of ventricular fibrillation during acute ischemia.
In fact, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction.
However, drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G. K., Circulation.
Conversion rates for these drugs range between 30-50% for recent onset AF (Capucci A., Aschieri D., Villani G. Q., Drugs &Aging 13(1):51-70, 1998), but they are also associated with a risk of inducing the ventricular tachyarrhythmias known as torsades de pointes.
Such events are particularly tragic in the case of AF as this arrhythmia is rarely a fatal in and of itself.

Method used

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  • Ion channel modulating compounds and uses thereof
  • Ion channel modulating compounds and uses thereof
  • Ion channel modulating compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

(±)-TRANS-[2-(4-MORPHOLINYL)-1-(2-NAPHTHENETHOXY)]CYCLOHEXANE MONOHYDROCHLORIDE

COMPOUND #1

(i) Morpholine (5 mL, 57 mmol), cyclohexene oxide (5.8 mL, 57 mmol) and water (3 mL) were refluxed for 1.5 h. GC analysis showed the reaction to be complete. The cooled mixture was partitioned between saturated NaOH solution (50 mL) and ether (75 mL). The aqueous layer was backwashed with ether (30 mL) and the combined ether layers were dried over sodium sulfate. The ether was removed in vacuo to leave a yellow oil (9.83 g). The crude product, (±)-trans-[2-(4-morpholinyl)]cyclohexanol, was purified by vacuum distillation (b.p. 75-80° C. at full vacuum) to give a clear liquid (8.7 g). Yield 82.5%.

(ii) To a chilled (0° C.) solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (6.0 g, 32.4 mmol) and triethylamine (6.8 mL, 48 mmol) in dichloromethane (100 mL) was added via cannula a solution of methanesulfonyl chloride (3.10 mL, 40 mmol) in dichloromethane (50 mL). The addition was completed i...

example 4

(±)-TRANS-[2-(4-MORPHOLINYL)-1-[2-(2-NAPHTHOXY)ETHOXY)]CYCLOHEXANE MONOHYDROCHLORIDE

COMPOUND #4

(i) The starting trans-aminocyclohexanol is prepared according to example 1.

(ii) To a chilled (0° C.) solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 mL, 24 mmol) in dichloromethane (50 mL) was added via cannula a solution of methanesulfonyl chloride (1.55 mL, 20.0 mmol) in dichloromethane (50 mL). The addition was completed in 10 min., the reaction mixture was stirred for another hour at 0° C. and then at room temperature for 4 hours. The dichloromethane mixture was washed with water (2×50 mL) and the combined aqueous washings back extracted with dichloromethane (50 in 10 min., the reaction mixture was stirred for another hour at 0° C. and then at room temperature for 4 hours. The dichloromethane mixture was washed with water (2×50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic la...

example 5

(±)-TRANS-[2-(4-MORPHOLINYL)-1-[2-(4-BROMOPHENOXY)ETHOXY)]]CYCLOHEXANE MONOHYDROCHLORIDE

COMPOUND #5

(i) The starting trans-aminocyclohexanol is prepared according to example 1.

(ii) To a chilled (0° C.) solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (3.0 g, 16.2 mmol) and triethylamine (3.4 mL, 24 mmol) in dichloromethane (50 mL) was added via cannula a solution of methanesulfonyl chloride (1.55 mL, 20.0 mmol) in dichloromethane (50 mL). The addition was completed in 10 min., the reaction mixture was stirred for another hour at 0° C. and then at room temperature for 4 hours. The dichloromethane mixture was washed with water (2×50 mL) and the combined aqueous washings back extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 3.95 g (92% yield) of the crude mesylate.

(iii) To sodium hydride, 80% oil dispersion, previously washed with hexanes (3×10 mL), (0.63 g, 26 mmol) in dry dimethylformami...

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Abstract

Ion channel modulating compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses a variety of in vitro and in vivo uses for the compounds and compositions, including the treatment of arrhythmia and the production of analgesia and local anesthesia.

Description

TECHNICAL FIELD The present invention is generally directed toward ion channel modulating compounds, pharmaceutical compositions and kits containing the ion channel modulating compounds, and therapeutic uses thereof. BACKGROUND OF THE INVENTION Cardiac ion channels are proteins that reside in the cell membrane and control the electrical activity of cardiac tissue. In response to external stimuli, such as changes in potential across the cell membrane, ion channels can form a pore through the cell membrane, and allow movement of specific ions into or out of the cell. The integrated behavior of thousands of ion channels in a single cell results in an ion current, and the integrated behavior of many ion currents makes up the characteristic cardiac action potential. Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are kno...

Claims

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Application Information

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IPC IPC(8): C07D295/08A61KA61K31/13A61K31/133A61K31/135A61K31/40A61K31/4015A61K31/407A61K31/41A61K31/4162A61K31/426A61K31/495A61K31/535A61K31/5375A61K31/5377A61P3/10A61P9/00A61P9/02A61P9/04A61P9/06A61P9/10A61P9/12A61P15/00A61P15/10A61P17/14A61P21/00A61P21/04A61P23/00A61P25/00A61P25/06A61P25/28A61P27/02A61P29/00A61P37/06C07CC07C217/52C07DC07D207/04C07D207/12C07D207/24C07D207/26C07D207/27C07D277/04C07D295/096C07D295/15C07D295/18C07D295/185C07D333/54C07D333/56C07D491/10C07D491/113
CPCC07C217/52C07C2101/14C07D207/12C07D207/27C07D277/04C07D295/08C07D491/10C07D295/14C07D295/15C07D295/185C07D333/54C07D333/56C07D295/096C07C2601/14A61P1/00A61P1/04A61P11/00A61P11/06A61P11/14A61P13/00A61P13/10A61P15/00A61P15/10A61P17/00A61P17/14A61P19/02A61P21/00A61P21/04A61P23/00A61P25/00A61P25/04A61P25/06A61P25/08A61P25/16A61P25/22A61P25/24A61P25/28A61P27/02A61P29/00A61P3/00A61P3/10A61P37/00A61P37/06A61P37/08A61P5/00A61P9/00A61P9/02A61P9/04A61P9/06A61P9/10A61P9/12
Inventor BAIN, ALLAN I.BEATCH, GREGORY N.LONGLEY, CINDY J.PLOUVIER, BERTRAND M. C.SHENG, TAOWALKER, MICHAEL J. A.WALL, RICHARD A.YONG, SANDRO L.ZHU, JEFF JIQUNZOLOTOY, ALEXANDER B.
Owner CORREVIO INT SARL
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