WO2004098525A2 - Utilisations de composes modulant les canaux ioniques - Google Patents

Utilisations de composes modulant les canaux ioniques Download PDF

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Publication number
WO2004098525A2
WO2004098525A2 PCT/US2004/013731 US2004013731W WO2004098525A2 WO 2004098525 A2 WO2004098525 A2 WO 2004098525A2 US 2004013731 W US2004013731 W US 2004013731W WO 2004098525 A2 WO2004098525 A2 WO 2004098525A2
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Prior art keywords
ion channel
channel modulating
hydrogen
subject
modulating compound
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PCT/US2004/013731
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English (en)
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WO2004098525A9 (fr
WO2004098525A3 (fr
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Gregory N. Beatch
Alan Ezrin
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Cardiome Pharma Corp.
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Priority to CA002524034A priority Critical patent/CA2524034A1/fr
Publication of WO2004098525A2 publication Critical patent/WO2004098525A2/fr
Publication of WO2004098525A9 publication Critical patent/WO2004098525A9/fr
Publication of WO2004098525A3 publication Critical patent/WO2004098525A3/fr
Priority to US11/832,580 priority patent/US20080063707A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms

Definitions

  • the methods and formulations described in this patent relate to the use of ion channel modulating compounds to treat or prevent arrhythmia and other diseases. Specific plasma level concentrations, dosage levels and other characterizations of ion channel modulating compounds used to treat or prevent arrhythmia and other diseases, and in particular atrial fibrillation, are described.
  • Atrial flutter and atrial fibrillation are the most commonly sustained cardiac arrhythmias in clinical practice. In this patent we refer to atrial fibrillation as either "atrial fibrillation" or "A .”
  • ED emergency department
  • Atrial fibrillation there are a variety of management strategies for acute atrial fibrillation and the outcomes are generally good; however, catastrophic events can occur as a result of atrial fibrillation such as congestive heart failure, thrombo-embolic phenomenon (particularly strokes), and serious adverse effects associated with treatment.
  • arrhytmias such as atrial fibrillation
  • atrial fibrillation Treatment of arrhytmias such as atrial fibrillation is complex and aspects of care, especially the decision to control the ventricular rate vs. convert the arrhythmia, remain controversial. Conversion of atrial fibrillation to sinus rhythm is often attempted in the acute setting to improve symptoms and to prevent the detrimental hemodynamic effects that atrial fibrillation may have in some patients (e.g., valvular disease or left ventricular dysfunction). Early conversion of atrial fibrillation may also prevent the development of electrical remodeling and the embolic risks associated with intra-atrial thrombus formation. Electrical cardioversion is effective in restoring sinus rhythm but requires procedural sedation or anesthesia and is not successful in all cases.
  • Described in this patent are methods, formulations, dosing regimes, and routes of administration for the treatment or prevention of various diseases or conditions, including arrhythmias, and particularly the treatment or prevention of atrial fibrillation.
  • the disease or condition is treated or prevented by administering one or more ion channel modulating compounds to a subject, where the ion channel modulating compound or compounds produce specific plasma levels in the subject.
  • methods for providing specified plasma levels of ion channel modulating compounds in a subject are described in detail in the Detailed Description section. In one version of the methods, the subject is a human subject.
  • the formulation is an intravenous formulation.
  • the formulation is an oral formulation.
  • the formulations may include one or more ion channel modulating compounds together with other optional components.
  • the fo ⁇ nulations may be administered in a variety of dosing regimes, including administering one or more formulations ⁇ that may or may not be administered via the same route of administration.
  • the formulations may also be delivered by repeat dosing and by substantially continuous dosing.
  • the plasma levels may be characterized using a variety of characterizations, including (1) that die characterization that the concentration is above some concentration level for some amount of time, (2) that the C max of the concentration profile is above some specified level or in some range of levels, (3) that the mean trough value is below some specified level or is in a range of levels, and (4) that the steady state value is below some specified level or is in a range of levels.
  • Examples of blood plasma level concentration profiles that may be produced using the methods described in this patent include those in which the concentration of the ion channel modulating compound or compounds (1) is greater than about 0.1 g/ml for at least some time; (2) has a C max of greater than about 0.1 g/ml; (3) has a C max of between about 0.3 ⁇ g/ml and about 20 ⁇ g/ml; (4) has a C ma ⁇ of between about 0.3 ⁇ g/ml and about 15 ⁇ g/ml; (5) is greater that about 0.1 ⁇ g/ml for a period of time of at least about 10 hours; (6) is greater that about 1.0 ⁇ g/ml for a period of time of at least about 2 hours; (7) has a mean trough concentration of less than about 20 ⁇ g/ml; (8) has a steady state concentration of less than about 20 ⁇ g/ml; (9) has a mean trough concentration of less than about 10 ⁇ g/ml; (10) has a
  • the ion channel modulating compound or compounds are administered to the subject to produce a total ion channel modulating compound concentration that (1) is greater than about 0.1 ⁇ g/ml for at least some time; (2) has a C max of greater than about 0.1 ⁇ g/ml; (3) has a C max of between about 0.3 ⁇ g/ml and about 20 ⁇ g/ml; (4) has a Cmax of between about 0.3 ⁇ g/ml and about 15 ⁇ g/ml; (5) is greater that about 0.1 ⁇ g/ml for a period of time of at least about 10 hours; or (6) is greater that about 1.0 ⁇ g/ml for a period of time of at least about 2 hours.
  • the total ion channel modulating compound concentration may possess one or more of these characterizations.
  • the ion channel modulating compound or compounds are administered to the subject to produce a total ion channel modulating compound concentration that (1) has a mean trough concentration of less than about 20 ⁇ g/ml; (2) has a steady state concentration of less than about 20 ⁇ g/ml; (3) has a mean trough concentration of less than about 10 ⁇ g/ml; (4) has a steady state concentration of less than about 10 ⁇ g/ml; (5) has a mean trough concentration of between about 0.3 ⁇ g/ml and about 10 ⁇ g/ml; (6) has a steady state concentration of between about 0.3 ⁇ g/ml and about 10 ⁇ g/ml; (7) has a mean trough concentration of between about 0.3 ⁇ g/ml and about 3 ⁇ g/ml; (8) has a steady state concentration of between about 0.3 ⁇ g/ml and about 3 ⁇ g/ml;
  • ion channel modulating compounds that may be used in the methods provided in this patent are described in detail in the Detailed Description section.
  • the ion channel modulating compound may be a compound of formula
  • R 4 and R 5 are independently selected from hydrogen, hydroxy and C ⁇ -C 6 alkoxy.
  • the ion channel modulating compound is a monohydrochloride salt of the formula
  • the ion channel modulating compound is a cycloalkylamine ether compound of formula
  • n 1,2,3, or 4 and the other substituents are as defined in the Detailed Description
  • Figure 1 illustrates a reaction sequence whereby certain aminocyclohexyl ether compounds of the present invention may be synthesized.
  • Figure 2 shows the cumulative percentage of dissolution of an intermediate release form of the ion channel modulating compound (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride over time.
  • Figure 3 shows a comparison of the cumulative percentage of dissolution of different controlled release formulations of the ion channel modulating compound (IR, 2R)-2-[(3R)- hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride over time.
  • Figure 4 shows the cumulative percentage of patients terminating atrial fibrillation (AF) after infusions of placebo, 0.5 and 1 mg/kg (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l- (3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride or 2.0 and 3.0 mg/kg (IR, 2R)- 2-[(3R)-hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride, in patients with recent onset atrial fibrillation.
  • AF atrial fibrillation
  • Figure 5 shows the plasma concentrations of (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]- l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride after infusion in patients dosed at 2 mg/kg i.v. (filled inverted triangles) and those additionally dosed at 3 mg kg i.v. (filled circles).
  • Figure 6 shows (IR, 2R)-2-[(3R)-hydroxy ⁇ yrrolidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride plasma concentrations at various times after IV (10-min infusion) or oral drug administration (solution in orange juice) to normal volunteers (dose 5 mg/kg).
  • Figure 7 shows individual Plasma Concentration of (IR, 2R)-2-[(3R)- hydroxypyrrolidinyl]- 1 -(3 ,4-dimethoxyphenethoxy)cyclohexane monohydrochloride Versus Time Following Oral Gavage Administration in Beagle Dogs.
  • Figure 8 shows individual Plasma Concentration of (IR, 2R)-2-[(3R)- hydroxypyrrolidinyl] - 1 -(3 ,4-dimethoxyphenethoxy)cyclohexane monohydrochloride Versus Time Following Intraduodenal Administration in Beagle Dogs.
  • Figure 9 shows individual Plasma Concentration of (IR, 2R)-2-[(3R)- hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride Versus Time Following Intracolonic Administration in Beagle Dogs.
  • Figure 11 shows dose normalized AUCs of (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l- (3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride for each route of administration in beagle dogs.
  • Figure 12 shows the plasma concentration levels of of (IR, 2R)-2-[(3R)- hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride after a single oral dose in six dog subjects.
  • Figure 13 shows the plasma concentration levels of of (IR, 2R)-2-[(3R)- hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride after a single oral dose in six dog subjects following seven days of repeated (4x daily) dosing of the drug.
  • Figure 14 shows the trough (Cmin) plasma concentration levels of of (IR, 2R)-2- [(3R)-hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride for six dog subjects given repeated daily dosing of the drug.
  • Figure 15 shows a simulation of the pharmacokinetics of a 100 mg oral dose.
  • Figure 16 shows a simulated pharmacokinetic profile for a multiple dosing regime of 100 mg given orally every two hours.
  • Figure 17 shows a simulated pharmacokinetic profile for a multiple dosing regime of a loading dose of 500 mg followed by a maintence dose of 100 mg given orally every two hours.
  • Figure 18 shows a simulated pharmacokinetic profile for a multiple dosing regime of a loading dose of 150 mg followed by a maintence dose of 100 mg given orally every two hours.
  • Figure 19 shows a simulation of a single oral dose of an immediate release drug formulation, four controlled release formulations: a hydrophilic drug formulaion, a 300 mg hydrophilic drug formulation, a hydrophobic drug formulation, and a hot-melt wax drug formulation.
  • Figure 20 shows a simulated pharmacokinetic profile for a multiple dosing regime of a a 300 mg hydrophilic drug formulation given orally every eight hours.
  • Figure 21 shows a simulated pharmacokinetic profile for a multiple dosing regime in which a loading dose of a 300 mg hydrophilic drug formulation is followed by a maintence dose of 100 mg given orally every eight hours.
  • Described in this patent are methods, formulations and routes of administration for achieving a blood plasma level of an ion channel modulating compound in a subject. Also described in this patent are methods, formulations and routes of administration for treating a subject suffering from arrhythmia by achieving a blood plasma level. Also described are methods, formulations, and routes of administration for preventing or postponing onset of arrhythmia in a subject by achieving a blood plasma level.
  • Atrial fibrillation is one type of arrhythmia specificially referred to throughout this description.
  • the methods, formulations and routes of administration described herein are not limited to atrial fibrillation, and may be used to treat, prevent and/or postpone the onset of any arrhythmia, including but not limited to: ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, premature ventricular contractions), supravent ⁇ icular arrhythmias (e.g., supraventricular tachycardia, atrial fibrillation, Wolff- Parkinson- White Syndrome, atrial flutter, premature supraventricular contractions), heart block, Long Q-T Syndrome, and sick sinus syndrome.
  • ventricular arrhythmias e.g., ventricular tachycardia, ventricular fibrillation, premature ventricular contractions
  • supravent ⁇ icular arrhythmias e.g., supraventricular tachycardia, atrial fibrillation, Wolff- Parkinson- White Syndrome, atrial
  • the subject in which arrhythmia or other diseases may be treated or prevented is any mammal.
  • the subject is a human subject.
  • the subject is any domestic animal, including but not limited to dogs, and cats.
  • the subject is any livestock animal, including but not limited to pigs, horses, cows and sheep.
  • the subject is any zoo animal, including but not limited to: Bengel tigers, camels and giraffes.
  • arrhythmia e.g. atrial fibrillation
  • formulations and routes of administration that maybe used in these methods.
  • methods for preventing or postponing onset of arrhythmia and formulations and routes of administration that may be used in these methods.
  • useful plasma levels and other diseases that it is believed may be treated using these plasma levels.
  • a subject suffering from arrhythmia including but not limited to atrial fibrillation, is treated by administering to the subject a formulation containing one or more ion channel modulating compounds.
  • the formulation may optionally contain one or more additional components.
  • treatment As used in this patent, unless the context makes clear.otherwise, “treatment,” and similar word such as “treated,” “treating” etc, is an approach for obtaining beneficial or desired results, including and preferably clinical results.
  • treatment preferably means termination of arrhythmia.
  • Treatment may also mean a return to normal sinus rhythm for the subject suffering from arrhythmia.
  • Treatment may also mean a lessening of the severity of the arrhythmia. Treatement may include the use of the methods, formulations and routes of administration described herein in conjunction with other therapies, for example, electrical cardioversion.
  • the arrhythmia treated is atrial fibrillation.
  • the subject in which arrhythmia may be treated is any mammal.
  • the subject is a human subject, h other versions the subject is a domestic animal, including but not limited to dogs and cats; or a farm animal, including but not limited to.
  • any ion channel modulating compound capable of treating arrhythmia may be used in the methods and formulations described in this section.
  • Specific ion channel modulating compounds that may be used are described in the Ion Channel Modulating Compounds section of this patent, and generally any of the ion channel modulating compounds described in that section may be used.
  • the ion channel modulating compound is (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride.
  • the formulation used for treating arrhythmia (e.g. atrial fibrillation) in the methods described in this patent can be a pure ion channel modulating compound, a mixture of one or more ion channel modulating compounds, a pure ion channel modulating compound formulated with one or more additional components, or a mixture of one or more ion channel modulating compounds formulated with one or more additional components.
  • the ion channel modulating compound or compounds may generally be any of the compounds as described in the Ion Channel Modulating Compounds section of this patent.
  • any formulation, route of administration, and dosage form capable of being used in the methods for treating arrhythmia described in this patent may be used.
  • the formulation is an oral dosage formulation or an intravenous dosage formulation.
  • An example of a formulation that may be used for treating arrhythmia is an intra- enous formulation of one or more ion channel modulating compound in a pharmaceutically acceptable solution.
  • the one or more ion channel modulating compound may generally be any ion channel modulating compound described in the Ion Channel Modulating Compounds section of this patent.
  • ion channel modulating compound that may be used is (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride.
  • a formulation that may be used to treat arrhythmia by intravenous administration is a 20 mg/ml (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy) cyclohexane monohydrochloride isotonic intravenous solution in 40 mM sodium Citrate, pH 5.5.
  • Other preferred formulations include immediate (fast or "flash”) release oral, sublingual, nasal, and inhaled formulations.
  • the formulation used for treatment of arrhythmia will contain an amount of the one or more ion channel modulating compounds such that administration of a dose of the formulation containing a therapeutically effective amount of the ion channel modulating compound or compounds will treat the arrhythmia in the subject.
  • a "therapeutically effective amount" of the one or more iori channel modulating compounds is that amount sufficient to effect the desired treatment of arrhythmia in the subject to which the one or more ion channel modulating compounds are administered.
  • the formulation containing the therapeutically effective amount of the ion channel modulating compound or compounds may be administered in repeated doses.
  • each individual does may or may not deliver a therapeutically effective amount of the ion channel modulating compound or compounds but the cumulative effect of the repeated doses will deliver a therapeutically effective amount of the ion channel modulating compound or compounds.
  • the formulation is administered in a dose delivering between about 0.1 mg/kg and about 10 mg/kg of the ion channel modulating compound or compounds or compounds to the subject.
  • the formulation is administered in a dose delivering between about 0.5 mg/kg and about 5 mg/kg of the ion channel modulating compound or compounds or compounds.
  • “mg/kg” means the amount of ion channel modulating compound or compounds per kg body weight of the subject.
  • the administered dose contains 5mg of ion channel modulating compound or compounds.
  • the formulation is delivered by repeat dosing where a first dose delivers between about 0.1 mg/kg and about 10 mgkg of ion channel modulating compound or compounds and a second dose delivers between about 0.1 mg/kg and about 10 mg/kg of ion channel modulating compound or compounds. These first two doses may optionally be followed by one or more subsequent doses.
  • the first dose delivers between about 0.1 mg/kg and 5.0 mg/kg of ion channel modulating compound or compounds and the second dose delivers between about 0.5 mg/kg and about 10 mg/kg of ion channel modulating compound or compounds; or the first dose delivers between about 1.0 mg/kg and about 5 mg/kg of ion channel modulating compound or compounds and the second dose delivers between about 1.0 mg/kg and about 5 mg kg of ion channel modulating compound or compounds.
  • the time between repeated dosing may generally be any time such that the repeated dosing delivers a therapeutically effective amount of the ion channel modulating compound or compounds.
  • the time between repeated doses may be between about 5 minutes and about 1 hour, or in another version between about 15 minutes and about 45 minutes.
  • repeated doses of between about 0.01 mg/kg and about 10 mg/kg are delivered per hour for up to 36 hours.
  • repeated doses do not have to be administered via the same route of administration. For example, a first dose may be administered intravenously followed by a second dose administered orally.
  • a therapeutically effective amount of the ion channel modulating compound or compounds may be delivered by administering more than one formulation at the same time.
  • a therapeutically effective amount of the ion channel modulating compound or compounds may be delivered by simultaneous or near simultaneous administration of both oral and intravenous formulations.
  • the concentration of the ion channel modulating compound or compounds present in the subject blood plasma after administration will be at a level sufficient to effect the required treatment of the subject's arrhythmia.
  • the blood plasma level is the concentration of the ion channel modulating compound or compounds in the blood plasma of the subject.
  • the blood plasma level of the ion channel modulating compound or compounds has a C max of at least 0.1 ⁇ g/ml during and/or following administration of one or more doses of the formulation.
  • the blood plasma level of the ion channel modulating compound or compounds has a C max of between about 0.3 ⁇ g/ml and about 20 ⁇ g/ml during and/or following administration of one or more doses. In one version, the blood plasma level of the ion channel modulating compound or compounds has a C max of between about 0.3 ⁇ g/ml and about 15 ⁇ g/ml during and/or following administration of one or more doses.
  • the blood plasma levels of the ion channel modulating compound or compounds is at least about 1 ⁇ g/ml for a time of about 2 hours during and/or following the administration of the first dose of formulation.
  • the blood plasma level of the ion channel modulating compound or compounds is at least about 0.1 ⁇ g/ml for a time of about 10 hours during and/or following the administration of the first dose of the formulation.
  • these blood plasma levels are maintained by administering two or more repeated doses of the specific intravenous formulation described above in this section.
  • a formulation containing one or more ion channel modulating compounds is administered to a subject to prevent or postpone onset of arrhythmia (e.g. atrial fibrillation) in the subject.
  • arrhythmia e.g. atrial fibrillation
  • Prevention and postponement of onset include prevention and postponement of onset of recurrence of arrhythmia; that is, the prevention or postponent of onset of arrhythmia in a subject that has previously undergone one or more arrhythmias.
  • the formulation may optionally contain one or more additional components.
  • prevention and similar word such as “prevented,” “preventing” etc, is an approach for obtaining beneficial or desired results, including and preferably clinical results.
  • prevention preferably means stopping the occurrence of arrhythmia. Prevention may also include not only an absolute stopping of the occurrence of arrhythmia but may also include a lessening of the severity of arrhythmia if it does occur. The methods described in this section may also be used to postpone the time for onset of arrhythmia if it does occur. The methods described in this section may also be used to lessen the probability that the subject will suffer from arrhythmia.
  • the arrhythmia to be prevented is atrial fibrillation.
  • the subject in which arrhythmia may be prevented or for which onset may be postponed is any mammal.
  • the subject is a human subject.
  • the subject is any domesic animal, including, but not limited to cats, dogs, etc.
  • the subject is any farm animal, inlcluding, but not limited to pigs, cows, horses, etc..
  • any ion channel modulating compound capable of preventing or postponing onset of arrhythmia may be used in the methods and formulations described in this section.
  • Specific ion channel modulating compounds that may be used are described in the Ion Channel Modulating section of this patent, and generally any of the ion channel modulating compounds described in that section may be used.
  • the ion channel modulating compound is (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride .
  • the formulation used for preventing or postponing onset of arrhythmia in the methods described in this patent can be a pure ion channel modulating compound, a mixture of one or more ion channel modulating compounds, a pure ion channel modulating compound formulated with one or more additional components, or a mixture of one or more ion channel modulating compounds formulated with one or more additional components.
  • the ion channel modulating compound or compounds may generally be any of the compounds as described in the Ion Channel Modulating Compounds section of this patent.
  • any formulat on, route of administration, and dosage form capable of being used in the methods for preventing or postponing onset of arrhythmia described in this patent maybe used.
  • General formulations, routes of administration, and dosage forms that maybe used are described in the Formulations, Routes of Administration, and Dosage Forms section in the patent.
  • Specific nonlimiting examples of formulations, routes of administration, and dosage forms that may be used for preventing or postponing onset of arrhythmia using the methods described in this patent are described in more detail below in this section.
  • the formulation is an oral dosage formulation.
  • An example of a formulation that may be used for preventing or postponing onset of arrhythmia is an oral dosage formulation of one or more ion channel modulating compound.
  • the oral dosage formulation may be a solid formulation or may be a liquid formulation.
  • the one or more ion channel modulating compound may generally be any ion channel modulating compound described in the Ion Channel Modulating Compounds section of this patent.
  • a specific example of an ion channel modulating compound that may be used is (IR, 2R)-2- [(3R)-hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride.
  • a formulation that may be used to prevent or postpone onset arrhythmia by oral administration is a controlled release (CR) formulation, described below.
  • the formulation used for preventing or postponing onset of arrhythmia will contain an amount of the one or more ion channel modulating compounds such that administration of a dose of the formulation containing a therapeutically effective amount of the ion channel modulating compound or compounds will prevent or postpone onset of the arrhythmia in the subject.
  • a "therapeutically effective amount" of the one or more ion channel modulating compounds is that amount sufficient to effect the desired prevention or postponement of onset of arrhythmia in the subject to which the one or more ion channel modulating compounds are administered.
  • the formulation containing the therapeutically effective amount of the ion channel modulating compound or compounds may be administered in repeated doses.
  • each individual does may or may not deliver a therapeutically effective amount of the ion channel modulating compound or compounds but the cumulative effect of the repeated doses will deliver a therapeutically effective amount of the ion channel modulating compound or compounds or compounds.
  • the formulation is administered in a dose delivering between about 0.1 mg/kg and about 50 mg/kg per day of the ion channel modulating compound or compounds or compounds to the subject, hi another version, the formulation is administered in a dose delivering between about 0.5 mg/kg and about 20 mg/kg per day of the ion channel modulating compound or compounds or compounds. In another version, the formulation is administered in a dose delivering between about 5.0 mg/kg and about 20 mg/kg per day of the ion channel modulating compound or compounds or compounds.
  • the formulation is delivered by repeat dosing where a first dose delivers between about 0.1 mg/kg and about 10 mg/kg of the ion channel modulating compound or compounds or compounds and a second dose delivers between about 0.1 mg/kg and about 10 mg/kg of the ion channel modulating compound or compounds or compounds. These first two doses may optionally be followed by one or more subsequent doses.
  • the first dose delivers between about 0.1 mg/kg and 5.0 mg/kg of the ion channel modulating compound or compounds and the second dose delivers between about 0.5 mg/kg and about 10 mgkg of the ion channel modulating compound or compounds or compounds; or the first dose delivers between about 1.0 mg/kg and about 3 mg/kg of the ion channel modulating compound or compounds or compounds and the second dose delivers between about 1.0 mg/kg and about 5 mg/kg of the ion channel modulating compound or compounds or compounds.
  • the time between repeated dosing may generally be any time such that the repeated dosing delivers a therapeutically effective amount of the ion channel modulating compound or compounds.
  • the time between repeated doses maybe between about 5 minutes and about seven days, or in another version between about 1 hour and about 24 hours. In one version, the time between repeated doses is between about 4 hours and about every seven days, or in another version between about 8 horus and 24 hours. In one version the time between doses is about 12 hours.
  • repeated doses do not have to be administered via the same route of administration. For example, a first dose may be administered orally followed by a second dose administered intravenously.
  • a therapeutically effective amount of the ion channel modulating compound or compounds may be delivered by administering more than one formulation at the same time. As a nonlimiting example, a therapeutically effective amount of the ion channel modulating compound or compounds may be delivered by simultaneous or near simultaneous administration of both oral and intravenous formulations.
  • the concentration of the ion channel modulating compound or compounds present in the subject blood plasma after administration will be at a level sufficient to effect the required prevention or postponement of onset of the subject's arrhythmia (e.g. atrial fibrillation);
  • the blood plasma level of the ion channel modulating compound or compounds has a C max of at least 50 ng/ml following administration of one or more doses of the formulation.
  • the blood plasma level of the ion channel modulating compound or compounds has a C max of between about 50 ng/ml and about 50 ⁇ g/ml following administration of one or more doses.
  • the blood plasma level of the ion channel modulating compound or compounds following administration of one or more doses has a C max of between about 50 ng/ml and about 30 ⁇ g/ml; or between about 50 ng/ml and about 20 ⁇ g/ml; or between about 50 ng/ml and about lO ⁇ g/ml; or between about 0.3 ⁇ g/ml and about 3 ⁇ g/ml; or between about 1 O ⁇ g/ml and about 50 ⁇ g/ml; or between about 20 ⁇ g/ml and about 50 ⁇ g/ml; or between about 30 ⁇ g ml and about 50 ⁇ g/ml.
  • the blood plasma levels of the ion channel modulating compound or compounds is at least about 0.1 ⁇ g/ml for a time of about 3 hours during and/or following the administration of the first dose of formulation. In one nonlimiting example, these blood plasma levels are maintained by administering one or more repeated doses of the oral formulation described above in this section.
  • the blood plasma levels of the ion channel modulating compound or compounds has a mean trough value of between about 50 ng ml and about 30 ⁇ g/ml.
  • the mean trough value is between about 50 ng/ml and about 20 ⁇ g/ml.
  • the mean trough value is between about 50 ng/ml and about lO ⁇ g/ml.
  • the mean trough value is between about 1 ng/ml to 10 ⁇ g/ml.
  • the mean trough value is between about 0.3 ⁇ g/ml and about 3 ⁇ g/ml.
  • the mean trough value is the average of the trough values for the blood plasma levels of the ion channel modulating compounds during a course of dosing; where the trough value is the lowest concentration of the ion channel modulating compound in the blood plasma immediately before a subsequent dose of the ion channel modulating compound.
  • the mean trough value for the course of closing illustrated in Figure 18 is the average of the seven local minimum values of the blood plasma levels immediately preceeding doses two through eight of the ion channel modulating compounds.
  • the methods of treatment or methods of prevention it may be possible to provide blood plasma levels by a continuous or substantially continuous delivery of the ion channel modulating compounds.
  • the characterization of the total concentration of ion channels modulating compounds by the mean trough levels is ambiguous since there are not a discrete number of doses with concomitant trough levels immediately preceding each dose.
  • the continuous or substantially continuous delivery of ion channel modulating compound will provide, after some initial time, a steady state concentration of ion channel modulating compound or compounds.
  • the ranges of mean trough valves described for the multiple dosing regime is replaced by ranges for the steady state concentration.
  • the steady state concentration is less than about 20 ⁇ g/ml. In another version, the steady state concentration is less than about 10 ⁇ g/ml. In another version, the steady state concentration is between 1 ng/ml and 10 ⁇ g/ml. In another version, the steady state concentration is between 0.3 ⁇ g/ml and 3 ⁇ g/ml.
  • the ion channel modulating compound or compounds that are administered to a subject have a rate of abso ⁇ tion that is substantially independent of the site or route of administration.
  • the rate of absorption of the ion channel modulating compound or compounds administered to a subject orally is approximately equivalent to the rate of absorption of the ion channel modulating compound or compounds administered in the duodenum of the subject.
  • the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered to a subject orally is approximately equivalent to the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered in the colon of the subject.
  • the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered to a dog is substantially independent of the site or route of administration. In one version, the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered to a dog orally is approximately equivalent to the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered in the duodenum of the dog. In one version, the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered to a dog orally is approximately equivalent to the rate of abso ⁇ tion of the ion channel modulating compound or compounds administered in the colon of the dog.
  • the blood plasma level of the ion channel modulating compound or compounds is substantially independent of the route of administration.
  • the blood plasma level of the ion channel modulating compound or compounds following oral administration to the subject is substantially equivalent to the blood plasma level of the ion channel modulating compound or compounds following administration to the subject's colon.
  • the blood plasma level of the ion channel modulating compound or compounds following oral administration to the subject is substantially equivalent to the blood plasma level of the ion channel modulating compound or compounds following administration to the subject's duodenum.
  • the subject is a dog.
  • the rate of abso ⁇ tion of the ion channel modulating compound or compounds may be measured by the blood plasma level of the ion channel modulating compound or compounds over time. In one version, the rate of abso ⁇ tion of the ion channel modulating compound or compounds is measured by the area under the curve (AOC) of the blood plasma level of the ion channel modulating compound or compounds over time. In one version, the rate of abso ⁇ tion of the ion channel modulating compound or compounds is measured by the peak blood plasma level (C ma ⁇ ) of the ion channel modulating compound or compounds and the time after administration that the peak blood plasma level occurs (T ma ⁇ )-
  • a second rate of abso ⁇ tion is substantially equivalent to a first rate of abso ⁇ tion if the value of the second rate of abso ⁇ tion is within about twenty percent of the value of the first rate of abso ⁇ tion, or within about ten percent of the value of the first rate of abso ⁇ tion, or within about five percent of the value of the first rate of abso ⁇ tion.
  • a second blood plasma level is substantially equivalent to a first blood plasma level if the value of the second blood plasma level is within about twenty percent of the value of the first blood plasma level, or within about ten percent of the value of the first blood plasma level, or within about five percent of the value of the first blood plasma level.
  • the blood plasma levels of ion channel modulating compounds maybe used to treat or prevent arrythmias including atrial fibrillation.
  • the . blood plasma levels of ion channel modulating compounds may be used to treat or prevent other diseases. Examples of diseases which it is believed may be teated are described in this section.
  • Useful blood plasma levels in a subject of ion channel modulating compounds in a subject include: (l)greater than about 0.1 ⁇ g/ml for at least some time; (2)C max greater than about 0.1 ⁇ g/ml; (3)C ma ⁇ between about 0.3 ⁇ g/ml and about 20 ⁇ g/ml; (4)C ma ⁇ between about 0.3 ⁇ g/ml and about 15 ⁇ g/ml; (5)greater that about 0.1 ⁇ g/ml for a period of time of at least about 10 hours; (6)greater that about 1.0 ⁇ g/ml for a period of time at least about 2 hours; (7)mean trough less than about 20 ⁇ g/ml; (8)steady state concentration less than about 20 ⁇ g/ml; (9)mean trough less than about 10 ⁇ g/ml; (10)steady state concentration less than about 10 ⁇ g/ml; (1 l)mean trough concentration between about 1 ng/ml
  • the above blood plasma levels are useful when provided in a human subject.
  • the above blood plasma levels are also useful when provided in a dog or pig subject. It is believed that the above blood plasma levels may also be useful when produced in other subjects such as those described elsewhere in this patent.
  • the blood plasma levels described in this section may be produced in a subject by administering to the subject one or more channel modulating compounds in an amount sufficient to produce the blood plasma levels described.
  • any formulations, routes of administration, and closing regimes capable of producing the blood plasma levels may be used.
  • General examples of formulations routes of administration and dosages that maybe used are described in the Formulations, Routes of Administration and Dosage section.
  • Specific, nonmniting formulations, routes of administration and dosage regimes that may be used to produce the blood plasma levels are described in the examples and in the method of treating and method of preventing sections above. With this information, together with their knowledge of the field, someone with knowledge of drug delievery technologies will be able to straightforwardly produce the described blood plasma levels in a subject.
  • the blood plasma levels described in this section may be used to treat or prevent arrythmias, including but not limited to atrial fibrillation.
  • the ion channel modulating compounds at the blood plasma levels described may also be used to treat or prevent other diseases including at least the following diseases and conditions: disease of tlie central nervous system (CNS disorders), Lou Gehrig's disease (Amyotrophic Lateral Sclerosis), Alzheimer, AIDS-related dementia, Multiple Sclerosis (MS), convulsion, seizures, epileptic spasms, depression, insomnia, anxiety, schizophrenia, Parkinson's disease, trigeminal pain, phantom limb pain, back pain, smoke cessation, respiratory disorders, cystic fibrosis, asthma, cough, inflammation and inflammatory disorders, irritable bowel disorders, irritable bowel syndrome Crohn's disease, prostatic hype ⁇ lasia, insect bites, psoriasis, arthritis, allergies, gastrointestinal disorders, urinary incontinence, cardio-vascular disorders, arrhythmia, heart failure, hypotension, cerebral or myocardial ischemias, hypertension, long-QT syndrome, stroke, migraine, ophthalmic diseases, diabetes mellitus
  • the methods and formulations described herein may be used for at least the following treatments: antitoxin, anti-venom, antiviral, antibiotic, antiparasitic, antineoplastic, antinociceptive, sedative, anesthetic, analgesic, painkiller, painkiller, antipsychotic, local anaesthetic, topical anesthetic, antiangiogenic, cardioplegia, cardioprotectant.
  • the unique combination of activity with affect on the atria and devoid of or substantially devoid of similar effects on the ventricle leads to the development of an agent that may be used for the treatment and/or prevention of electrical rhythm disturbances in the atria without subsequent effects on the electrical activity in the ventricle.
  • the methods and ion channel modulating compounds described in this, patent application are proposed for use in diseases and conditions including without limitation the management of atrial fibrillation, flutter and other supraventricular rhythm disturbance without adverse effects or substantial adverse effects on the electrical activity and rhythm of the ventricles.
  • an ion channel modulating compound is administered to treat and/or prevent diseases and conditions including without limitation a host of supraventicular rhythm disturbances whilst not affecting or substantially affecting the ventricles and being a safer agent for patients with impaired LV function and useful for managing rate and rhythm disturbances in acute MI and CHF.
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions by modulating the late sodium current.
  • the late sodium current may also be referred to as the persistent sodium current.
  • an ion channel modulating compound is administered to treat and/or prevent and/or diagnose diseases or conditions in which the late sodium current is enhanced.
  • an ion channel modulating compound is administered to treat and/or prevent and/or diagnose diseases or conditions in which the late sodium current is enhanced in skeletal muscle.
  • an ion channel modulating compound is administered to treat and/or prevent and/or diagnose congenital myotonia.
  • an ion channel modulating compound is administered to treat and/or prevent acute rhythm disturbances in the heart under pathological conditions (i.e. acute ischemia) in which normal electrophysiology of the heart is altered and under which I & is of minimal importance and repolarization time course is dominated by I t0 and/or I ur - h
  • acute rhythm disturbances in the heart resulting from slowing conduction e.g reentrant arrhythmia under acute ischemia or other disease state
  • a therapeutically effective amount of a composition effective to treat and/or prevent and/or diagnose acute rhythm disturbances in the heart under pathological conditions is given to a patient in need thereof.
  • an ion channel modulating compound is administered to treat and/or prevent rhythm disorders in the ischemic heart where such rhythm disturbances are mediated by prolonging refractoriness mediated by I ur and I t0 thusly prolonging the voltage time course of repolarization.
  • an ion channel modulating compound is administered to treat and/or prevent rhythm disorders of the heart by inhibiting sodium currents of excitation and prolonging refractoriness mediated by I ur and I t0 .
  • an ion channel modulating compound is administered to treat and/or prevent and/or diagnose rhythm disturbances by affecting abnormal conduction and prolonging the voltage time course of repolarization.
  • an ion channel modulating compound is administered to treat and/or prevent rhythm disturbances by inhibiting sodium currents of excitation, inhibiting inward Na current associated with the plateau of the cardiac action potential (i.e.
  • an ion channel modulating compound is administered to treat and/or prevent and/or diagnose rhythm disturbances by affecting abnormal conduction and prolonging the voltage time course of repolarization.
  • an ion channel modulating compound is administered to treat and/or prevent rhythm disorders in patients in need thereof wherein the ion channel modulating compound is used in conjunction with devices (i.e. pacemakers or implantable defibrillators) to facilitate the patients response to the device to restore normal rhythm and that are used to manage patients with rhythm disturbances.
  • devices i.e. pacemakers or implantable defibrillators
  • an ion channel modulating compound is administered to treat and/or prevent the early return of atrial fibrillation following electrical cardioversion.
  • an ion channel modulating compound is administered to treat and/or prevent and/or diagnose the early return of atrial fibrillation following electrical cardioversion to improve the ease of cardioversion in patients requiring transthroacic or internal cardioversion to restore normal rhythm.
  • an ion channel modulating compound is administered to improve atrial contractility and/or to treat and/or prevent blood stasis via electrical stunning following a cardiac procedure.
  • cardiac procedures include but are not limited to the maze procedure , surgery or cardiac bypasss, or any other procedure in which the atria are stunned precluding effective mechanical function leading to blood statsis, clotting, and potential of thromobosis.
  • an ion channel modulating compound is administered to diagnose, treat and/or prevent electrical abnormalities of the heart in patients suffering from impaired electrical conduction of the heart.
  • an ion channel modulating compound is administered to diagnose, treat and/or prevent contractile dysfunction and/or stunning of the atria, hi one version of the methods described in this patent application an ion channel modulating compound is administered to reduce thrombosis, cardiac and cerebral ischemia due to atrial dyskenesis and clot formation in patients suffering from impaired electrical and mechanical function of the heart. [00100] In one version of the methods described in this patent application an ion channel modulating compound is administered to treat and/or diagnose vasoconstriction.
  • an ion channel modulating compound is administered to treat and/or prevent vasoconstriction in patients with reduced blood flow based upon inhibition of I to and I kur - hi
  • an ion channel modulating compound is administered to treat and/or prevent vasoconstriction by improving blood flood to selected organs and tissues.
  • an ion channel modulating compound is administered to treat and/or prevent vasospasm.
  • an ion chaimel modulating compound is administered to improve respiratory function based upon relaxation of smooth muscle mediated by blockade of I t0 and I ur resulting in improvements in airway flow.
  • an ion chamiel modulating compound is administered to treat and/or prevent smooth muscle spasm.
  • an ion channel modulating compound is administered to improve renal function and urinary flow based upon relaxation of smooth muscle mediated by blockade of I t0 and I ur resulting in improvements in urine flow.
  • an ion channel modulating compound is administered to improve gall bladder function and bile flow based upon relaxation of smooth muscle mediated by blockade of I t0 and I kur - [00103]
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions which are mediated by inhibiting sodium currents and potassium currents.
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions which are mediated by inhibiting sodium currents and potassium currents by inhibiting sodium channels and I kur and/or I t0 .
  • an ion channel modulating compound is administered to improve smooth muscle contractile function in body structures associated with physiological processes.
  • physiological processes include but are not limited to the passage of fluids and material through the body in the gut, urinary, respiratory or circulatory system for the reduction in blood pressure , intraocular pressure, humoral flow associated with glaucoma.
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions of the blood.
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions of the blood by modifying Ikur or I t0 .
  • diseases or conditions of the blood include but are not limited to sickle cell anemia and abnormal leukocyte or lymphochyte function (e.g. abnormal leukocyte or lymphochyte function associated with limiting an inflammation and/or immune response, particularly those mediated by changes in I ur or I t0 ).
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions of low flow ischemia, shock and/or reperfusion injury.
  • an ion channel modulating compound is administered to treat and/or prevent diseases or conditions of low flow ischemia, shock and/or reperfusion injury by inhibiting sodium currents and potassium currents mediated by I kur and I to .
  • an ion channel modulating compound is provided as an enzyme modulator.
  • Enzyme that may be modulated may include but are not limited to lactate dehydrogenase (LDH); kinases such as map kinases and other kinases; transaminase; ATPase; xanthine oxidase; and Cytochrome oxidase.
  • LDH lactate dehydrogenase
  • kinases such as map kinases and other kinases
  • transaminase such as map kinases and other kinases
  • transaminase such as map kinases and other kinases
  • transaminase such as map kinases and other kinases
  • transaminase such as map kinases and other kinases
  • transaminase such as map kinases and other kinases
  • transaminase such as map kinases and other kinases
  • transaminase such as map kinases and other
  • an ion channel modulating compound is provided as an anti-helminthic or vermifuge, i.e. de- worming medication for human or other mammals.
  • an ion channel modulating compound is administered to influence heart rate or rhythm. In one version of the methods described in this patent application an ion channel modulating compound is administered to influence heart rate or rhythm in the normal heart. In one version of the methods described in this patent application an ion channel modulating compound is administered to influence heart rate or rhythm in the diseased heart. [00109] In one version of the methods described in this patent application an ion channel modulating compound is used as a research tool or diagnostic tool. In one version of the methods described in this patent application an ion channel modulating compound is used as a research tool or diagnostic tool by modulating I t0 and I ur and I ⁇ a .
  • an ion channel modulating compound is used as a research tool or diagnostic tool based on its association with the protein or molecules mediating I to and I ur and lN a .
  • an ion channel modulating compound is used as a ligand or affinity probe for proteins or molecules (i.e. ion channels).
  • an ion channel modulating compound is used as a research tool or diagnostic tool to create antibodies.
  • an ion channel modulating compound is used as a research tool or diagnostic tool to identify cellular or subcellular processes associated with cardiac function. In one version of the methods described in this patent application an ion channel modulating compound is used as a research tool or diagnostic tool to identify receptor function and/or signal transduction. In one version of the methods described in this patent application an ion channel modulating compound is used as a research tool or diagnostic tool to identify mechanisms associated with disease of the body (such as cardiac disorders).
  • Modulating Compounds and Exemplary Ion Channel Modulating Compounds all enantiomeric and diastereomeric forms of the ion channel modulating compounds are intended. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different ion channel modulating compounds are described. Thus, the.ion channel modulating compounds may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
  • Acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid,
  • Alkanoyloxy refers to an ester substituent wherein the ether oxygen is the point of attachment to the molecule.
  • Alkoxy refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH , a alkoxy ⁇ .
  • Alkoxyalkyl refers to a alkylene group substituted with an alkoxy group.
  • methoxyethyl [CH 3 OCH 2 CH 2 -] and ethoxymethyl (CH 3 CH 2 OCH 2 -] are both
  • Alkyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include n-propyl (a C 3 alkyl), ⁇ -propyl (also a C 3 alkyl), and t-butyl (a C 4 alkyl).
  • Alkylene refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment.
  • An example is propylene [-CH 2 CH 2 CH 2 -, a alkylene].
  • Alkylcarboxy refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl
  • Aryl refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups, all of which may be optionally substituted.
  • Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups.
  • Aralkyl refers to an alkylene group wherein one of the points of attachment is to an aryl group.
  • An example of an aralkyl group is the benzyl group [C 6 H 5 CH 2 -, a
  • Cycloalkyl refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms.
  • An example of a cycloalkyl group is the cyclopentenyl group (C 5 H 7 -), which is a five carbon (C5) unsaturated cycloalkyl group.
  • Carbocyclic refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
  • Carbocyclic aryl refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted.
  • Heteroatom refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.
  • Heteroaryl refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in
  • Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
  • Hydroxyalkyl refers to a branched or unbranched hydrocarbon fragment bearing an hydroxy (-OH) group. Examples include hydroxymethyl (-CH 2 OH, a Cihydroxyalkyl) and 1-hydroxyethyl (-CHOHCH 3 , a C 2 hydroxyalkyl).
  • Thioalkyl refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH 3 S-, a Cithioalkyl).
  • Modulating in connection with the activity of an ion channel means that the activity of the ion channel may be either increased or decreased in response to administration of a compound or composition or method of the present invention.
  • the ion channel may be activated, so as to transport more ions, or may be blocked, so that fewer or no ions are transported by the channel.
  • “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences. Mack Publishing Co. (A.R. Gennaro edit. 1985).
  • sterile saline and phosphate-buffered saline at physiological pH may be used.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of / hydroxybenzoic acid may be added as preservatives. Id at 1449.
  • antioxidants and suspending agents may be used. Id.
  • “Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts).
  • the compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.
  • Aminocyclohexyl Ether Ion Channel Modulating Compounds [00136]
  • One class of compounds that are ion channel modulating compounds are compounds that comprise an aminocyclohexyl ether core structure having an ether oxygen atom at position 1 of a cyclohexane ring, and an amine nitrogen atom at position 2 of the cyclohexane ring. This core structure is shown below, with other positions numbered in corresponding order:
  • bonds from the cyclohexane ring of A to the 1 -oxygen and 2-nitrogen atoms in the above formula may be relatively disposed in either a cis or trans relationship.
  • the stereochemistry of the amine and ether substituents of the cyclohexane ring is either (R,R)-trans or (S,S)-trans.
  • the stereochemistry at these positions is either (R,S)-cz ' s or (S,R)-c s.
  • the ion channel modulating compound is a compound of the formula:
  • Compounds of formula (I) are aminocyclohexyl ethers. More specifically, these aminocyclohexyl ethers are substituted at position 2 of the cyclohexyl ring with an amine group -NR]R 2 .
  • the cyclohexyl ring may also be substituted with additional substituents (designated as R 3 and R 4 ) as described in more detail below. Examples of specific compounds represented by formula (I) are described below.
  • the compounds of formula (I) may be primary, secondary, or tertiary amines (i.e., both Ri and R 2 are hydrogen, only one of Ri and R 2 is hydrogen, or neither of Rj and R 2 are hydrogen, respectively).
  • the compounds of formula (I) are tertiary amines, i.e., neither Ri nor R is hydrogen. Where the amine is tertiary, it may be a cyclic amine.
  • Amine substituents Ri and R 2 may be independently selected from substituents which include hydrogen, alkyl groups containing from one to eight carbon atoms (i.e., C ⁇ -C 8 alkyl), alkoxyalkyl groups containing from three to eight carbon atoms (i.e., C 3 -C 8 alkoxyalkyl), alkyl groups containing from one to eight carbon atoms where one of the carbon atoms is substituted with a hydroxyl group (i.e., C ⁇ -C 8 hydroxyalkyl), and aralkyl groups containing from seven to twelve carbon atoms (i.e., C 7 -C ⁇ 2 aralkyl).
  • substituents which include hydrogen, alkyl groups containing from one to eight carbon atoms (i.e., C ⁇ -C 8 alkyl), alkoxyalkyl groups containing from three to eight carbon atoms (i.e., C 3 -C 8 alkoxyalkyl), alkyl groups containing from one to
  • Ri and R 2 are independently selected from hydrogen, C ⁇ -C 8 alkyl, C 3 -C 8 alkoxyalkyl, C ⁇ -C 8 hydroxyalkyl, and C 7 -C ⁇ 2 aralkyl. In another version, Ri and R 2 are independently selected from C 3 -C 8 alkoxyalkyl, C ⁇ -C 8 hydroxyalkyl, and C 7 -C ⁇ 2 aralkyl.
  • Ri and R 2 when taken together with the nitrogen atom to which they are directly attached in formula (I), may form a ring denoted by formula (IT):
  • the ring of formula (IT) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C ⁇ -C 3 hydroxyalkyl, oxo, C 2 -C acyl, C ⁇ -C 3 alkyl, C 2 -C alkylcarboxy, C r C 3 alkoxy, C ⁇ -C 2 oalkanoyloxy, or maybe substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur (e.g., an acetal, thioacetal, ketal, or thioketal group); and any two adjacent additional carbon ring atoms may be fused to a C 3
  • any two adjacent ring atoms may be joined together by single or double bonds.
  • the ring of formula (fl) may be saturated or unsaturated, and an unsaturated ring may contain one, or more than one, sites of unsaturation.
  • the ring of formula (II) may contain one or more double bonds, it being understood, however, that the unsaturated ring of formula (II) is chemically stable.
  • Ri and R 2 when taken together with the 2-amino nitrogen of formula (I), may complete a bicyclic ring.
  • Bicyclic rings include, for example,
  • 3-azabicyclo[3.2.0]heptane 3-azabicyclo[3.2.0]heptane.
  • 2-substituents of the cyclohexyl ethers of formula (I) are the following groups: 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo-
  • R t and R 2 when taken together may contain only a single heteroatom.
  • Preferred heteroatoms include nitrogen, oxygen and sulfur.
  • An example of a ring in which Ri and R 2 together include an oxygen heteroatom is the mo ⁇ holinyl group.
  • An example of a ring where Rj and R 2 together include a second nitrogen heteroatom is the piperazinyl group.
  • Cyclohexane substituents R 3 and R4 may be independently attached to ring positions 3, 4, 5 or 6 (i.e., both R 3 and R 4 may be attached to the same ring position or each attached to different ring positions).
  • R 3 and Rt are independently selected from hydrogen, hydroxy, Ci-C ⁇ alkyl, and Ci-C ⁇ alkoxy, and, when both R 3 and are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur.
  • Preferred heterocyclic substituents contain either a single oxygen or a single sulfur ring atom.
  • the ether side chain, -CH(R 5 )-X-A, in formula (I) may take several forms.
  • a compound of formula (I) may have X as a
  • Y may be any of a direct bond, an oxygen atom (O), a sulfur atom (S) or a Ci-C 4 alkylene group.
  • Re and R ]4 are independently selected from hydrogen,
  • Ci-C ⁇ alkyl, aryl and benzyl, or R ⁇ and R ⁇ 4 when taken together with the carbon to which they are attached, may form a spiro C 3 -C 5 cycloalkyl.
  • compounds of the invention include compounds of formula (I) where Re and R 14 are hydrogen and Y is a direct bond, such that X maybe CH 2 .
  • X may be an alkenylene moiety, e.g., a cz ' s-or tr ⁇ ns-alkenylene moiety,
  • R ]3 maybe any of hydrogen, Ci-C ⁇ alkyl, C 3 -C 8 cycloalkyl, aryl or benzyl.
  • X is an alkenylene moiety
  • X is preferably a tr ⁇ ns-alkenylene moiety.
  • X may be a direct bond.
  • R 5 is selected from hydrogen, C ⁇ -C 6 alkyl, aryl and benzyl.
  • the compounds of the invention exclude those compounds wherein X is a direct bond when Ri and R 2 are hydrogen.
  • the compounds of the invention exclude those compounds wherein X is a direct bond when A is formula (DT) and each of R 7 , R 8 and R 9 is hydrogen. In another variation, the compounds of the invention exclude those compounds wherein X is a direct bond when A is formula (IH).
  • Ether side chain component A is generally a hydrophobic moiety.
  • a hydrophobic moiety is comprised of non-polar chemical groups such as hydrocarbons or hydrocarbons substituted with halogens or ethers or heterocyclic groups containing nitrogen, oxygen, or sulfur ring atoms.
  • Suitable hydrocarbons are C 5 -C ⁇ 2 alkyl and C 3 -C 1 carbocyclic rings.
  • Particularly preferred cyclic hydrocarbons include selected aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, indenyl, acenaphthyl, and fluorenyl and are represented by formulae (IH), (TV), (V), (VI), (VH), or (VTfi) respectively.
  • a suitable "A” group in the formula above is a phenyl ring represented by formula
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl,
  • R15 and Rj 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and C ⁇ -C 6 alkyl.
  • R , R 8 and R 9 is preferably selected from amine (-NR 1 5R16, where R 15 and R ⁇ 6 are independently hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl), bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-C ⁇ alkyl,
  • Ci-Cealkoxy C 2 -C alkylcarbonyl, C ⁇ -C ⁇ thioalkyl or aryl groups.
  • the present invention provides compounds of formula (I) where A includes phenyl groups of formula (rffl) such that at least one of R 7 , R 8 and R 9 is not hydrogen, i.e., formula (fll) is a phenyl group that contains at least one non-hydrogen substituent.
  • R 7 , R 8 and R 9 are selected from amine
  • Ci-C ⁇ alkyl bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-Cealkyl, Ci-C ⁇ alkoxy, C 2 -C 7 alkylcarbonyl -and d-C ⁇ thioalkyl, i.e., none of R 7 , R 8 or R 9 is aryl.
  • A does not include a phenyl ring of formula (IH) when X is a direct bond.
  • Rio and R ⁇ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C alkanoyloxy, Ci-Cealkyl, -C ⁇ alkoxy, C 2 -C 7 alkoxycarbonyl, Ci-C ⁇ thioalkyl, and N(Ri5,Ri ⁇ ) where R ⁇ 5 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl.
  • Rio and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl,
  • R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl, as defined above.
  • R ⁇ 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy,
  • the aryl groups of formula (VI) are derivatives of indene, indole, benzofuran, and thianaphthene when Z is methylene, nitrogen, oxygen, and sulfur, respectively.
  • Preferred heterocyclic groups of formula (VI) include indole where Z is NH, benzofuran where Z is O, and thianaphthene where Z is S.
  • Z is O, S or N-R ⁇ , and in a particularly preferred embodiment Z is O or S.
  • Another suitable "A” group is acenaphthyl groups as represented by formula (VII):
  • Still another suitable "A” group is the fluorenyl group represented by formula (VET):
  • ether side chain component A is an acenapthyl or fluorenyl group only when X is a direct bond or CH 2 .
  • the acenaphthyl group is a
  • the fluorenyl group is a 9-fluorenyl group.
  • X is (CH 2 )-Y.
  • Y is preferably a direct bond, an oxygen atom, or a sulfur atom.
  • Y is a direct bond or an oxygen atom.
  • Y is a direct bond and X is
  • R 6 C(R6,R ⁇ 4 ), where Re and R ⁇ 4 are as defined above.
  • Rn is a hydrogen atom.
  • R 3 and Ri may be independently attached to the cyclohexane ring at the 4- or 5- positions.
  • the ion channel modulating compound is a compound of the formula (I), wherein: independently at each occurrence,
  • R ⁇ 3 is selected from hydrogen, Ci-C ⁇ alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl;
  • Ri and R 2 are independently selected from hydrogen, C ⁇ -C 8 alkyl, C 3 -C 8 alkoxyalkyl, C ⁇ -C 8 hydroxyalkyl, and C -C] 2 aralkyl; or
  • Ri and R 2 are independently selected from C 3 -C 8 alkoxyalkyl, Cj- C 8 hydroxyalkyl, and C 7 -C] 2 aralkyl; or
  • ring of formula (I ) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C ⁇ -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C ⁇ -C 3 alkyl, C 2 -C 4 alkylcarboxy, C ⁇ -C 3 alkoxy, C]-C 2 oalkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be
  • Ri and R 2 when taken together with the nitrogen atom to which they are directly attached in formula (I), may form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl;
  • R 3 and t are independently attached to the cyclohexane ring shown in formula (I) at the 3-, 4-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, Ci-C ⁇ alkyl and Ci-Cealkoxy, and, when both R 3 and R are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur;
  • R 5 , Re and R ⁇ 4 are independently selected from hydrogen, Ci-Cealkyl, aryl and benzyl, or R 6 and R ⁇ 4 , when taken together with the carbon to which they are attached, may form a spiro -Cscycloalkyl;
  • A is selected from Cs-C ⁇ alkyl, a C 3 -C ⁇ 3 carbocyclic ring, and ring systems selected from formulae (DT), (TV), (V), (VI), (VII) and (VDT):
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C ⁇ -C 6 alkyl, Ci-C ⁇ alkoxy, C 2 -C 7 alkoxycarbonyl, Cj-C ⁇ thioalkyl and N(R 15 ,Ri 6 ) where Ru and Rj 6 are independently selected from hydrogen, acetyl, methanesulfonyl and C ⁇ -C 6 alkyl;
  • R] 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-Cealkyl, Ci-C ⁇ alkoxy, C 2 -C 7 alkoxycarbonyl, Ci-Cethioalkyl, and N(Ri 5 ,R 1 ⁇ ) where R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R ⁇ when Z is N, and R ⁇ is selected from hydrogen, Ci-Cealkyl, C 3 -C 8 cycloalkyl, aryl and benzy
  • VD VD
  • VDT VDT
  • the ion channel modulating compound is a compound of the formula (TX), or a solvate or pharmaceutically acceptable salt thereof:
  • Y is selected from a direct bond, O and S;
  • Ri, R 2 , R 3 , R 4 , Re, R 7 , R 8 , R , Rio, i R12, R ⁇ 4 , A and Z are defined as above for compounds of formula (I).
  • the ion channel modulating compound is a compound of the formula (X), or a solvate or pharmaceutically acceptable salt thereof:
  • Y is selected from a direct bond, O, and S;
  • Ri, R 2 , R and R 14 are defined as above for compounds of formula (I);
  • R 3 and Ri are independently attached to the cyclohexane ring at the 4- or 5-positions, and are independently selected from hydrogen and C ⁇ -C 6 alkoxy;
  • A is selected from C 5 -C 12 alkyl, C 3 -C 8 cycloalkyl, and any of formulae (ID),
  • R 12 are defined as above for compounds of formula (I).
  • the ion channel modulating compound is a compound of the formula (XI), or a solvate or pharmaceutically acceptable salt thereof:
  • Ri and R 2 are defined as above for compounds of formula (I);
  • R 3 and R are independently attached to the cyclohexane ring at the 4- or 5-positions, and are independently selected from hydrogen and methoxy;
  • A is selected from Cs-C ⁇ alkyl, C 3 -C 8 cycloalkyl, and any of formulae (DT),
  • R 12 are defined as above for compounds of formula (I).
  • the ion channel modulating compound is a compound of the formula (X ⁇ ), or a solvate or pharmaceutically acceptable salt thereof:
  • Ri and R 2 are defined as above for compounds of formula (I);
  • R 3 are independently attached to the cyclohexane ring at the 4- or 5- ⁇ ositions, and are independently selected from hydrogen and methoxy;
  • A is selected from C 5 -C ⁇ 2 alkyl, C 3 -C 8 cycloalkyl, and any of formulae (HI),
  • R 12 are defined as above for compounds of formula (I).
  • the ion channel modulating compound is a compound of the formula (XDT), or a solvate or pharmaceutically acceptable salt thereof:
  • Y, Ri, R 2j Re and Rj 4 are defined as above for compounds of formula (I);
  • R 3 and 1 ⁇ are independently attached to the cyclohexane ring at the 4- or 5 -positions, and are independently selected from hydrogen and methoxy;
  • A is selected from C 3 -C 8 cycloalkyl and any of formulae (DT), (IV), (V), (VI),
  • the ion channel modulating compound is a compound of the formula (XTV), or a solvate or pharmaceutically acceptable salt thereof:
  • Ri and R 2 are defined as above for compounds of formula (I);
  • A is selected from any of formulae (DT), (IV), (V) and (VI) as above for compounds of formula (I), wherein R 7 , Rio, Rn, and R ⁇ 2 , are hydrogen, R 8 and R 9 are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH 2 , with the proviso that at least one of
  • Rs and R 9 is not hydrogen; and Z is selected from O and S.
  • the ion channel modulating compound is a compound of the formula (XV), or a solvate or pharmaceutically acceptable salt thereof:
  • Ri and R 2 are defined as above for compounds of formula (I);
  • A is selected from any of formulae (DT), (IV), (V) and (VI) as defined above for compounds of formula (I), wherein R , R] 0 , R ⁇ , and R ⁇ 2 , are hydrogen, R 8 and R 9 are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH 2 , with the proviso that at least one of
  • Rs and R is not hydrogen; and Z is selected from O and S.
  • the ion channel modulating compound is a compound of the formula (XVT), or a solvate or pharmaceutically acceptable salt thereof:
  • Ri and R 2 are both methoxyethyl or, when taken together with the nitrogen atom to which they are attached, complete a ring selected from py ⁇ olidinyl, 2- ketopyrrolidinyl, 3-ketopyrrolidinyl, 2-acetoxypyrrolidinyl, 3-acetoxypyrrolidinyl, 2- hydroxypyrrolidinyl, 3-hydroxypyrrolidinyL thiazolidinyl, piperidinyl, 2-ketopiperidinyl, 3- ketopiperidinyl, 4-ketopiperidinyl, acetylpiperazinyl, l,4-dioxa-7-azaspiro[4.4]non-7-yl, hexahydroazepinyl, mo ⁇ holinyl, N-methylpiperazinyl and 3-azabicyclo[3.2.2]nonanyl; and
  • A is selected from cyclohexyl, monochlorophenyl, 2,6-dichlorophenyl,
  • the ion channel modulating compound is a compound of the formula (XVD), or a solvate or pharmaceutically acceptable salt thereof:
  • n is selected from 1, 2 and 3;
  • Ri 8 is either hydrogen or metliyl and is independently attached to the cyclohexane ring shown in formula (XVD) at one of the 3-, 4-, 5- or 6- positions;
  • R 9 is selected from a group consisting of bromine, chlorine, fluorine and hydrogen.
  • R 2 o is selected from a group consisting of bromine, chlorine and fluorine; including isolated enantiomeric, diastereomeric and geometric isomers thereof.
  • the ion channel modulating compound is a compound that is a trans configuration of formula
  • n is selected from 1, 2 and 3;
  • Ri 8 is either hydrogen or methyl and is independently attached to the cyclohexane ring shown in formula (XVH) at one of the 3-, 4-, 5- or 6- positions; R19 is selected from a group consisting of bromine, chlorine, fluorine and hydrogen; and
  • R20 is selected from a group consisting of bromine, chlorine and fluorine; including isolated enantiomeric, diastereomeric and geometric isomers thereof.
  • the ion channel modulating compound is a compound of the formula (IXX); or a solvate or pharmaceutically acceptable salt thereof:
  • n is selected from 1, 2 and 3;
  • Ris is either hydrogen or methyl and is independently attached to the cyclohexane ring shown in formula (XVD) at one of the 3-, 4-, 5- or 6- positions;
  • R ⁇ 9 is selected from a group consisting of bromine, chlorine, fluorine and hydrogen.
  • R 2 o is selected from a group consisting of bromine, chlorine and fluorine; including isolated enantiomeric, diastereomeric and geometric isomers thereof.
  • tlie ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof:
  • the ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt thereof, wherein, and R 5 are independently selected from hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, 4 and R 5 are independently selected from hydroxy and Ci-C ⁇ alkoxy.
  • the ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R 4 and R 5 are independently selected from Ci-C ⁇ alkoxy.
  • the ion chamiel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, P ⁇ and R 5 are independently selected from C ⁇ -C 6 alkoxy.
  • the ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R 4 and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XX), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, Rj and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or
  • R 3 , * and R 5 are independently selected from hydrogen, hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt thereof, wherein, R 4 and R 5 are independently selected from hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, t and R 5 are independently selected from hydroxy and Ci-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, and R 5 are independently selected from Ci-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, j and R 5 are independently selected from Ci-C ⁇ alkoxy.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXI), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, j and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof:
  • R 3 , R and R 5 are independently selected from hydrogen, hydroxy and Ci-Cealkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XX ⁇ ), or a solvate, pharmaceutically acceptable salt thereof, wherein, R 4 and R 5 are independently selected from hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R is hydrogen, ⁇ and R 5 are independently selected from hydroxy and Ci-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R$ and R 5 are independently selected from Ci-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, t and R 5 are independently selected from Cj-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, t and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXD), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R 4 and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXID), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or
  • R 3 , t and R $ are independently selected from hydrogen, hydroxy and Ci-Cealkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXTfl), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXDT), or a solvate, pharmaceutically acceptable salt thereof, wherein, t and R 5 are independently selected from hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXDT), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R is hydrogen, R and R 5 are independently selected from hydroxy and Ci-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXDT), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R 4 and R 5 are independently selected from Ci-Cealkoxy.
  • the ion chamiel modulating compound is compound of formula (XXDI), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R and R 5 are independently selected from Cj-Cealkoxy.
  • the ion channel modulating compound is compound of formula (XXDT), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, R 4 and R5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXDT), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 3 is hydrogen, t and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXIV), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or
  • t and R5 are independently selected from hydrogen, hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXIV), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXIV), or a solvate, pharmaceutically acceptable salt thereof, wherein, Rt and R are independently selected from hydroxy and Ci-C ⁇ alkoxy, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • the ion channel modulating compound is compound of formula (XXIV), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R and R 5 are independently selected from hydroxy and C ⁇ -C 3 alkoxy.
  • the ion channel modulating compound is compound of formula (XXTV), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 4 and R 5 are independently selected from
  • the ion channel modulating compound is compound of formula (XXIV), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R and R 5 are independently selected from C ⁇ -C 3 alkoxy.
  • the ion channel modulating compound is compound of formula (XXIV), or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amo ⁇ hous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 4 and R 5 are Ci alkoxy.
  • the ion channel modulating compound is compound of formula (XXTV), or a solvate, pharmaceutically acceptable salt thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, wherein, R 4 and R 5 are Ci alkoxy.
  • the ion channel modulating compound is a compound of the formula (XXV),
  • R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy and Ci-Cealkoxy; or,
  • R 3 are independently selected from hydroxyl and Ci-C ⁇ alkoxy and R 5 is hydrogen; or,
  • R 3 , R are both Ci-Cealkoxy and R5 is hydrogen; or
  • R 3 , R 4 are both methoxy and R 5 is hydrogen; or including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen; and r ⁇ indicates a bond that provides a R stereoisomer or a S stereoisomer at the position to which the bond is attached.
  • the hydroxyl substituent is positioned at the 3 position of the pyrrolidinyl ring in (XXV).
  • the stereochemistry at the position of the cycloalkyl ring of (XXV) containing the nitrogen group is racemic, which may be provided for any of the variations mentioned above.
  • the ion channel modulating compound is a compound of the formula (XXVI):
  • the — bond to the ether oxygen indicates that the ether and amine groups attached to the cyclohexyl group are in a trans configuration, and the C-l and C-2 carbons of the cyclohexyl group may be either R,R configuration or S,S configuration;
  • Ri and R 2 are independently selected from hydrogen, C ⁇ -C 8 alkyl, C 3 -C 8 alkoxyalkyl, Ci- Cshydroxyalkyl, and C 7 -Ci2aralkyl; or
  • R ⁇ and R2 are independently selected from C 3 -C 8 alkoxyalkyl, Ci-Cshydroxyalkyl, and C 7 -C ⁇ 2 aralkyl; or
  • Ri and R2 are taken together with the nitrogen atom to which they are directly attached in formula (XXvT) to form a ring denoted by formula (TV):
  • ring of formula (TV) wherein the ring of formula (TV) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C ⁇ -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, ⁇
  • C 3 alkyl, C 2 -C 4 alkylcarboxy, Ct-C 3 alkoxy, C ⁇ -C 2 oalkanoyloxy, or may be substituted to form a spiro five- or six membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional' carbon ring atoms may be fused to a
  • C 3 -C 8 carbocyclic ring and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, Ci-Cealkyl, C 2 -C 4 acyl, C 2 -
  • Ri and R 2 when taken together with the nitrogen atom to which they are directly attached in formula (XXVI), may form a bicyclic ring system selected from 3 azabicyclo[3.2.2]nonan 3 yl, 2 azabicyclo[2.2.2]octan 2 yl, 3 azabicyclo[3.1.0]hexan 3 yl and ' 3 azabicyclo[3.2.0]heptan 3 yl;
  • R 3 and R 4 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-Cealkyl, Ci-Cealkoxy, C 2 -C 7 alkoxycarbonyl, Ci-Cethioalkyl and N(Ri 5 ,R ⁇ e) where R ⁇ 5 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl and Ci-C ⁇ alkyl; and
  • R 3 and R 4 are independently selected from hydrogen, hydroxyl and Ci-Cealkoxy.
  • both R 3 and ⁇ t are Ci-Cealkoxy.
  • both R and t are methoxy.
  • R 3 and R 4 are positioned at the 3 and 4 positions of the aromatic ring, wherein the position on the aromatic ring containing the alkyl chain is designated the 1 position, this variation may be combined with any other variation mentioned above.
  • the ion channel modulating compound is a compound of the formula (XXVD), or pharmaceutically acceptable salts or solvates thereof.
  • the ion channel modulating compound is a compound of the formula (XXVDT),
  • the ion channel modulating compound is compound or any salt thereof, or any solvate thereof, or mixture comprising one or more said compounds or any salt thereof, or any solvate thereof, selected from the group consisting of:
  • compositions that includes one or more of the compounds or mixtures listed in the above table, or includes a solvate or a pharmaceutically acceptable salt of one or more of the compounds or mixtures listed in the above table.
  • the composition may or may not include additional components. Additional components that may be used are described elsewhere in detail in this patent.
  • the ion channel modulating compound is a compound or mixtare comprising compounds, or any solvate thereof, selected from the group consisting of:
  • compositions that includes one or more of the compounds or mixtures listed in the above table, or includes a solvate or a pharmaceutically acceptable salt of one or more, of the compounds or mixtares listed in the above table.
  • the composition may or may not include additional components. Additional components that may be used are described elsewhere in detail in this patent.
  • the ion channel modulating compound is one of the following compounds: (lR,2R)-2-[(3R)- Hydroxypyrrolidinyl]-l-(3,4-dimethoxyphenethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof; (lR,2R)-2-[(3S)-Hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof; (1 S,2S)-2-[(3R)-Hydroxy ⁇ yrrolidinyl]-l -(3,4-dimethoxyphenethoxy)-cyclohexane free base or any salt thereof, or any solvate thereof; (lS,2S)-2-[(3S)-Hydroxypyrrol
  • the ion channel modulating compound is a protenated version of any of the amino cyclohexyl ether compounds described in this patent. That is, for each amino cyclohexyl ether compound described in this patent, the quaternary protenated amine form of the compound may also be considered as an amino cyclohexyl ether ion channel modulating compounds. These quaternary protenated amine form of the compounds may be present in the solid phase, for example in crystalline or amo ⁇ hous form, and may be present in solution.
  • quaternary protenated amine form of the compounds may be associated with pharmaceutically acceptable anionic counter ions, including but not limited to those described in for example: "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002.
  • One class of compounds that are ion channel modulating compound comprise an aminocycloalkyl ether core structure having an ether oxygen atom at position 1 of a cycloalkyl ring, and an amine nitrogen atom at position 2 of the cycloalkyl ring.
  • the cycloalkyl ring is a 5, 7, or 8 membered ring.
  • the bonds from the cycloalkyl ring to the 1 -oxygen and 2-nitrogen atoms in the above formula may be relatively disposed in either a cis or trans relationship.
  • the stereochemistry of the amine and ether substituents of the cycloalkyl ring is either (R,R)-trans or (S,S)-trans.
  • the stereochemistry is either (R,S)-c s or (S,R)- «5.
  • the ion channel modulating compound is a compound of formula (IXXX):
  • the cycloalkyl ring may also be substituted with additional substitaents (designated as R 3 and R 4 ) as described in more detail below.
  • n is selected from 1, 3 and 4, and represents a number of carbon atoms such that when n equals 1, the ring shown in Formula (EXXX) is a substituted cyclopentane (i.e., a cyclopentyl group), when n equals 3, the ring shown in Formula (EXXX) is a substituted cycloheptane (i.e., a cycloheptyl group), and when n equals 4, the ring shown in Formula (EXXX) is a substituted cyclooctane (i.e., a cyclooctyl group). Examples of specific compounds represented by formula (EXXX) are described below
  • (EXXX) may be primary, secondary, or tertiary amines (i.e., both Ri and R 2 are hydrogen, only one of Ri and R 2 is hydrogen, or neither of Ri and R 2 are hydrogen, respectively).
  • Amine substitaents Ri and R 2 may be independently selected from substitaents which include hydrogen, alkyl groups containing from one to eight carbon atoms (i.e., C ⁇ -C 8 alkyl), alkoxyalkyl groups containing from three to eight carbon atoms (i.e., C 3 -C 8 alkoxyalkyl), alkyl groups containing from one to eight carbon atoms where one of the carbon atoms is substituted with a hydroxyl group (i.e., Ci-
  • Ri and R 2 when taken together with the nitrogen atom to which they are directly attached in formula (EXXX), may form a ring denoted by formula (D):
  • ring of formula (D) wherein the ring of formula (D) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C ⁇ -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C ⁇ -C 3 alkyl, C 2 -C 4 alkylcarboxy, C r C 3 alkoxy, C ⁇ -C 2 oalkanoyloxy, or maybe substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur (e.g., an acetal, thioacetal, ketal, or thioketal group); and any two adjacent additional carbon ring atoms maybe fused to
  • any two adjacent ring atoms may be joined together by single or double bonds.
  • the ring of formula (D) may be saturated or unsaturated, and an unsaturated ring may contain one, or more than one, sites of unsaturation.
  • the ring of formula (D) may contain one or more double bonds, it being understood, however, that the unsaturated ring of formula (D) is chemically stable.
  • Bicyclic rings include, for example,
  • Ri and R2 when taken together, contain only a single heteroatom.
  • Prefe ⁇ ed heteroatoms include nitrogen, oxygen and sulfur.
  • An example of a ring in which Ri and R2 together include an oxygen heteroatom is the mo ⁇ holinyl group.
  • An example of a ring where Ri and R 2 together include a second nitrogen heteroatom is the piperazinyl group.
  • Cycloalkyl substitaents R 3 and R4 may be independently attached to any of the ring positions except positions 1 and 2 (e.g., both R 3 and R 4 may be attached to the same ring position or each attached to different ring positions).
  • R 3 and R t are independently selected from hydrogen, hydroxy, Ci-Cealkyl, and Ci-Cealkoxy, and, when both R 3 and R 4 are attached to the same cycloalkyl ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur.
  • Preferred heterocyclic substitaents contain either a single oxygen or a single sulfur ring atom.
  • (EXXX) may take several forms.
  • a compound of formula (IXXX) may have X as a -C(Re,R ⁇ 4 )-Y- group, where Y may be any of a direct bond, an oxygen atom (O), a sulfur atom (S) or a C ⁇ -C 4 alkylene group.
  • Re and Rj 4 are independently selected from hydrogen,
  • Ci-Cealkyl, aryl and benzyl, or R 6 and R ⁇ 4 when taken together with the carbon to which they are attached, may form a spiro -Cscycloalkyl.
  • compounds of the invention include compounds of formula (EXXX) where R 6 and R ⁇ 4 are hydrogen and Y is a direct bond, such that X maybe CH 2 .
  • X may be an alkenylene moiety, e.g., a cis-o ⁇ tr ⁇ ws-alkenylene moiety,
  • R B may be any of hydrogen, Ci-Cealkyl, CrCscycloalkyl, aryl or benzyl.
  • X is preferably a tr ras-alkenylene moiety.
  • X may be a direct bond.
  • R 5 is selected from hydrogen, Ci-Cealkyl, aryl and benzyl.
  • Ether sidechain component A is generally a hydrophobic moiety.
  • a hydrophobic moiety is comprised of non-polar chemical groups such as hydrocarbons or hydrocarbons substituted with halogens or ethers or heterocyclic groups containing nitrogen, oxygen, or sulfur ring atoms.
  • Suitable hydrocarbons are Cs-C ⁇ 2 alkyl and C 3 -C ⁇ 3 carbocyclic rings.
  • Particularly preferred cyclic hydrocarbons include selected aromatic groups such as phenyl, 1 -naphthyl, 2-naphthyl, indenyl, acenaphthyl, and fluorenyl and are represented by formulae (ID), (EV), (V), (VI), (VD), or (VE ) respectively.
  • a suitable "A” group within the compounds of the present invention is a phenyl ring represented by formula (TIT):
  • R 7 , R 8 and R are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl,
  • R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-Cealkyl.
  • R 7 , R 8 and R 9 is preferably selected from amine (-NR 15 R1 6 , where Rj 5 and R ⁇ 6 are independently hydrogen, acetyl, methanesulfonyl, and Ci-Cealkyl), bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-Cealkyl, Ci-Cealkoxy, C 2 -C 7 alkylcarbonyl, Ci-Cethioalkyl or aryl groups.
  • R 7 , R 8 and R 9 are preferably a substituent other than hydrogen.
  • R 7 , R 8 and R 9 are preferably a substituent other than hydrogen.
  • Rio and R ⁇ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl,
  • R )5 and Ri ⁇ are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl.
  • Rio and R ⁇ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-Cealkyl, Ci-C ⁇ alkoxy, C 2 -C 7 alkoxycarbonyl, Ci-Cethioalkyl, and N(Ri 5 ,Ri 6 ) where R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl, as defined above.
  • Other suitable "A" groups in compounds of the present invention are aromatic groups represented by formula (VI):
  • R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy,
  • the aryl groups of formula (VI) are derivatives of indene, indole, benzofuran, and thianaphthene when Z is methylene, nitrogen, oxygen, and sulfur, respectively.
  • Preferred heterocyclic groups of formula (VI) include indole where Z is NH, benzofuran where Z is O, and thianaphthene where Z is S. As described below, in a preferred embodiment, Z is O, S or
  • N-R 17 and in a particularly preferred embodiment Z is O or S.
  • Another suitable "A” group in compounds of the present invention are acenaphthyl groups as represented by formula (Vfl):
  • Still another suitable "A” group in compounds of the present invention is the fluorenyl group represented by formula (VTfl):
  • ether sidechain component A is an acenapthyl or fluorenyl group only when X is a direct bond or CH 2 .
  • the acenaphthyl group is a 1 -acenaphthyl group
  • the fluorenyl group is a 9-fluorenyl group.
  • X is (CH 2 )-Y.
  • Y is a direct bond, an oxygen atom, or a sulfur atom.
  • Y is a direct bond or an oxygen atom.
  • R 3 and t are preferably independently attached to the cycloalkyl ring at the 4- or
  • Ion channel modulating compounds of formula (EXXX) maybe provided, wherein: independently at each occurrence, n is selected from 1, 3 and 4;
  • Q is either O (oxygen) or -O-C(O);
  • Y is selected from a direct bond, O, S and C ⁇ -C 4 alkylene
  • R 13 is selected from hydrogen, Ci-Cealkyl, C 3 -C 8 cycloalkyl, aryl and benzyl;
  • Ri and R 2 are independently selected from hydrogen, Ci-Csalkyl, C 3 -C 8 alkoxyalkyl, Ci-Cghydroxyalkyl, and C 7 -C ⁇ 2 aralkyl; or
  • Ri and R 2 are independently selected from C 3 -C 8 alkoxyalkyl, Ct- C 8 hydroxyalkyl, and C 7 -C ⁇ 2 aralkyl; or
  • Ri and R 2 are taken together with the nitrogen atom to which they are directly attached in formula (TXXX) to form a ring denoted by formula (El):
  • IE wherein the ring of formula (D) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may bear one or two substituents selected from hydrogen, hydroxyl, C ⁇ -C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C ⁇ -C 3 alkyl, C 2 -C alkylcarboxy, C 1 -C 3 alkoxy, C ⁇ -C 2 oalkanoyloxy, or may form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may bear substituents selected from hydrogen,
  • Ri and R 2 are taken together with the nitrogen atom to which they are directly attached in formula (EXXX) to form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl;
  • R 3 and t are independently attached to the cycloalkyl ring shown in formula (EXXX) at other than the 1 and 2 positions and are independently selected from hydrogen, hydroxyl, Ci-Cealkyl and Ci-Cealkoxy, and, when both R 3 and R 4 are attached to the same cycloalkyl ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur;
  • R 5 , Re and R ⁇ 4 are independently selected from hydrogen, Ci-C ⁇ alkyl, aryl and benzyl, or Re and R] 4 , when taken together with the carbon to which they are attached, may form a spiro C 3 -C 5 cycloalkyl;
  • A is selected from Cs-C ⁇ alkyl, a C 3 -C ⁇ 3 carbocyclic ring, and ring systems selected from formulae (ED), (EV), (V), (VI), (VD) and (VFD):
  • R , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C ⁇ -C 6 alkyl, Ci-Cealkoxy, C 2 -C 7 alkoxycarbonyl, Cj-Cethioalkyl, aryl and N(Ri5,R ⁇ 6 ) where R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl and Ci-C ⁇ alkyl;
  • V (FV) (V) where Rio and R ⁇ are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, CpCealkyl, Ci.-Cealkoxy, C 2 -C 7 alkoxycarbonyl, CpCethioalkyl, and N(R ⁇ s,Ri ⁇ ) where R 1 5 and Rie are independently selected from hydrogen, acetyl, methanesulfonyl, and -Cealkyl;
  • R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, Ci-C ⁇ alkyl, Ci-Cealkoxy, C 2 - 7 alkoxycarbonyl, Ci-Cethioalkyl, and (Ri5,Ri 6 ) where R15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and C ⁇ -C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown in formula (EXXX) when Z is CH or N, or Z may be directly bonded to R 17 when Z is N, and Rn is selected from hydrogen, Ci-Cealkyl, C 3 -C 8 cycloalkyl, aryl and benzyl
  • the ion channel modulating compound is one of the following compounds or mixtures of compounds.
  • the ion channel modulating compound is a protenated version of any of the amino cycloalkyl ether compounds described in this patent. That is, for each amino cycloalkyl ether compound described in this patent, the quaternary protenated amine form of the compound may also be considered as an amino cycloalkyl ether ion channel modulating compounds. These quaternary protenated amine form of the compounds may be present in the solid phase, for example in crystalline or amo ⁇ hous form, and may be present in solution.
  • quaternary protenated amine form of the compounds may be associated with pharmaceutically acceptable anionic counter ions, including but not limited to those described in for example: "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002.
  • any compound that modulates ion channel activity may by an ion channel modulating compound.
  • a compound that modulates ion channel activity may be a compound that increases or decreases ion channel activity.
  • An ion channel modulating compound that decreases ion channel activity may be a compound that blocks ion channel activity completely or partially.
  • any compound that either singly or together with one or more additional compounds selectively inhibit certain combination of cardiac ionic currents is an ion channel modulating compound.
  • the cardiac currents may be the sodium currents and early repolarizing cmrents.
  • Ion channel modulating compounds may block cardiac currents from extracellular loci. Such compounds act on an external locus of the ion channel that is accessible from the extracellular surface. This facilitates access to the ion channel and provides rapid onset kinetics and exhibits frequency dependent blockade of currents. Such properties are all beneficial for compounds used to treat arrhythmias.
  • An ion channel modulating compound may selectively inhibit cardiac early repolarizing currents and cardiac sodium currents.
  • Ion channel modulating compounds may be used to selectively inhibit cardiac early repolarizing 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 mo ⁇ hology, 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.
  • An ion channel modulating compound may be an atrial selective agent.
  • An ion channel modulating compound may treat or prevent ventricular arrhythmia.
  • An ion channel modulating compound block cardiac sodium cu ⁇ ents or cardiac early repolarizing currents.
  • An ion channel modulating compound may inhibit multiple cardiac ionic currents.
  • An ion channel modulating compound maybe used to treat or prevent archythmic, including ventricular or atrial arrhythmia, particularly atrial fibrillation.
  • the ion channel modulating compounds may block the cardiac ion channels responsible for early repolarizing currents and sodium currents; and/or block cardiac early repolarizing currents and cardiac sodium currents under conditions where an a ⁇ hythmogenic substrate is present in the heart; and/or block the cardiac ion channels responsible for early repolarizing currents and sodium currents under conditions where an a ⁇ hythmogenic substrate is present in the heart; and/or block cardiac early repolarizing cu ⁇ ents and cardiac sodium currents from extracellular loci in cardiac cells.
  • the cardiac early repolarizing currents refe ⁇ ed to above comprise ionic cu ⁇ ents which activate rapidly after depolarization of membrane voltage and which effect repolarization of the cell.
  • the early repolarizing cu ⁇ ents may comprise the cardiac transient outward potassium cu ⁇ ent (I t0 ) and/or the ultrarapid delay rectifier current ( )-
  • the cardiac transient outward potassium cu ⁇ ent (I 0 ) and/or the ultrarapid delay rectifier current (I ⁇ ur ) may comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kvl.4 and K.vl.5 currents.
  • Ion channel modulating compounds may generally have any pKa, however ion channel modulating compounds typically have pKa values of between 4-9, and may have pKa values that are less than 8, including pKa values between 5-7.5. Methods to determine pKa values are well known in the art (see, e.g., Perrin, "Dissociation Constants of Organic Bases in Aqueous Solution", Butterworth, London, 1972).
  • ion channel modulating compounds with the specific ranges of pKa described above, the fraction of the charged (protonated) species will be increased under the pathological conditions such as cardiac arrhythmias and the presence of an a ⁇ hythmogenic substrate in the heart as described above due to the increase in cardiac milieu acidity. Where the charged form of a compound is active, its potency increases under conditions associated with an increases in cardiac milieu acidity.
  • Particular ion channel modulating compounds have structural characteristics that may be determined by various physical methods, such as single crystal X-ray crystallography.
  • one of J and K comprises a hydrophobic moiety, such as but not limited to a moiety comprising alkyl and/or aryl moieties.
  • one of J and K comprises a hydrophobic aromatic moiety, which may be attached to the cycloalkane ring of structure T via an ether bond.
  • one of J and comprises a hydrophilic moiety, such as a heteroatom containing moiety, including but not limited to a nitrogen containing moiety that is available to form a quaternary salt and or a hydroxyl moiety.
  • one of J and K comprises a nitrogen containing moiety substitated with a hydroxyl moiety or the like, such as a pyrrolidinyl moiety.
  • n 2
  • J comprises a aromatic moiety
  • K comprises a nitrogen containing moiety substituted with a hydroxyl moiety or the like.
  • the cycloalkane ring may be optionally substituted.
  • the cycloalkane ring may be replaced by a structural moiety imparting rigidity to the relative positions of the J and K groups.
  • the ion channel modulating compound maybe a compound of formula where J and K are as described above and groups P and R are moieties such that there is not substantial rotation about the L-M bond.
  • P and Q taken together form a cyclic moiety that prevents substantial rotation about the L-M bond.
  • the ion channel modulating compound comprises an amino substituted 5, 6, 7 or 8-membered ring, which may be a 5, 6, 7, or 8-membered substitated or unsubstituted cycloalkyl ring.
  • the amino substituted cycloalkane ring may be an aminocyclohexyl ring and maybe further substitated with one or more additional moieties.
  • the amino substitated cycloalkane ring is further substituted with an ether moiety, hi some instances, the ion channel modulating compound comprises an aminocyclohexyl ring that is further substitated with an ether moiety.
  • the ion channel modulating compound is a protenated version of any of the ion channel modulating compounds described in this patent. That is, for each ion channel modulating compound described in this patent, the quaternary protenated amine form of the compound may also be considered as an amino ion channel modulating compound. These quaternary protenated amine form of the compounds may be present in the solid phase, for example in crystalline or amo ⁇ hous form, and maybe present in solution. These quaternary protenated amine form of the compounds may be associated with pharmaceutically acceptable anionic counter ions, including but not limited to those described in for example: "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002
  • the ion channel modulating compounds and formulations described herein may be formulated in a dosage form suitable for oral, parenteral, mucosal, nasal, sublingual, transdermal, buccal, topical, vaginal, rectal, ocular or other administration.
  • An ion channel modulating compounds as described herein may be in the form of an immediate and/or modified release formulation or it may be designed to release the ion channel modulating compound in a relatively fast manner in order to enable a relatively fast onset of the therapeutic effect.
  • “compounds” and “compositions" of ion channel modulating compounds includes the ion channel modulating compounds as described herein alone or in combination with other materials, as described below.
  • the amount of the ion channel modulating compound present in a composition depends inter alia on the specific ion channel modulating compound and formulation, the age and condition of the subject, and the disease or conditions to be treated and/or prevented, the route of administration, and the dosage frequency.
  • the dosage frequency also depends on the disease or condition to be treated and/or prevented, amount or concentration of the ion channel modulating compound, the specific composition used, the route of administration, and may inco ⁇ orate subject-specific variation including, but not limited to age, weight, gender, genetic background, and overall health.
  • a nasal formulation may be administered once daily e.g.
  • Formulations of the ion channel modulating compound can be used to provide controlled release ("controlled release formulations") in which the release of the ion channel modulating compound is controlled and regulated to allow less frequency of dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
  • controlled release formulations as described herein may allow dosage once, twice, or three or more times daily in order to obtain a suitable therapeutic effect.
  • Controlled release may also include continuous and/or sustained release, for example, as from an implantable device. Pulsatile release may also be desirable. Administration may comprise co- administration of more than one dosage unit, such as, e.g. 2-4 dosage units.
  • the ion channel modulating compounds described herein are formulated for use in humans. Ion channel modulating compounds can also include veterinary formulations, e.g., pharmaceutical preparations suitable for veterinary uses, e.g., for the treatment of livestock or domestic animals, e.g., dogs, cats, racehorses, etc.
  • Actual dosage levels of the ion channel modulating compound in the formulations of the ion channel modulating compounds described herein may be varied so as to obtain an amount of the ion channel modulating compound which is effective to achieve the desired therapeutic effect for a particular subject, ion channel modulating compound, and mode of administration, without being toxic to the subject.
  • the selected dosage level will depend upon a variety of factors including but not limited to the activity of the ion channel modulating compound (or the ester, salt, amide or formulation thereof); the route of administration; the time of administration; the rate of excretion of the particular ion channel modulating compound being employed; the duration of the treatment; other drugs, compounds and/or materials used in combination with the ion channel modulating compound described herein; the age, sex, weight, condition, general health and prior medical history of the subject being treated; and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the ion channel modulating compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired therapeutic effect is achieved.
  • a suitable dose of an ion channel modulating compound will be the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • Preferred formulations include oral (immediate or quick release forms) and intravenous forms (EV), nasal forms, sublingual and metered dose inhaler forms.
  • intravenous and oral forms of the ion channel modulating compound for a subject will range from about 0.1 to about 50 mg per kilogram of body weight per day.
  • a therapeutic dosage for the intravenous form may be from about 0.1 ( to about 10 mg per kilogram.
  • Another suitable dosage of (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride for the intravenous form may be from about 2 to about 5 mg per kilogram.
  • a therapeutic dosage for oral administration may be from about 30 to about 1800 mg tablets or capsules b.i.d.
  • Another suitable dosage of (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride for oral administration maybe from about 300 to about 900 mg tablets or capsules b.i.d.
  • intranasal formulations and patch formulations are also prefe ⁇ ed forms.
  • intranasal formulations and patch formulations of the ion channel modulating compound for a subject will range from about 0.1 to about 100 mg per kilogram of body weight per day, preferably from about 0.1 to about 10 mg per kilogram, even more preferably from about 1 to about 10 mg per kilogram. - ⁇
  • the effective dose of the ion channel modulating compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the subject receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets such as dogs and cats among others in general.
  • the ion channel modulating compound described herein may be administered to a subject by any route capable of delivering a therapeutically effective amount of the compound including but not limited to administration by oral, parenteral, intracranial, intraorbital, intracapsular, intraspinal, intracistemal, intrapulmonary, intravenous, intramuscular, intra- arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, buccal, gingival, palatal or rectal means.
  • the ion channel modulating compound is given in forms suitable for each administration route.
  • the ion channel modulating compound may be administered parenterally by injection, infusion or inhalation; administered topically by lotion or ointment; or administered rectally by suppositories.
  • Typical forms of administration described herein are not intended to be either limiting or exhaustive, but merely illustrative.
  • parenteral administration and “administered parenterally” as used herein mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • systemic administration or “administered systemically,” as used herein mean the administration of a compound, drug or other material such as the ion modulating compound so that it enters the subject's system by a direct route or parenteral route and thus is subject to metabolism and other like processes (for example, by subcutaneous administration).
  • peripheral administration and “administered peripherally” as used herein mean the administration of a compound, drug or other material such as the ion modulating compound so that it enters the subject's system by an indirect or localized route and thus is subject to metabolism and other like processes (for example, by topical administration).
  • the ion channel modulating compounds described herein can be formulated into pharmaceutically acceptable dosage forms such as described, or other dosage forms known to those of skill in the art.
  • phrases "pharmaceutically acceptable” as used herein can refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the ion channel modulating compounds can be administered alone or in admixtures with pharmaceutically acceptable and/or sterile carriers and can also be administered in conjunction with other drugs (e.g. other cardiovascular agents, antimicrobial agents, etc.). Multiple routes of simultaneous or sequential administration (e.g. oral and transdermal) are also contemplated.
  • Formulations of ion channel modulating compounds can be formulated in any manner suitable for a desired delivery route.
  • formulations include all physiologically acceptable compositions.
  • Such formulations may include one or more ion channel modulating compounds by itself or in combination with any physiologically acceptable carrier or carriers.
  • the formulation may also enhance, alter, or modify the effect or the ion channel modulating compound and/or physiological milieu of the ion channel modulating compound.
  • an ion channel modulating compound While it is possible for an ion channel modulating compound to be administered alone, it is preferable to administer the ion channel modulating compounds as a pharmaceutical formulation including other materials.
  • the ion channel modulating compounds may be formulated for administration in any way for use in human or veterinary medicine.
  • the ion channel modulating compound may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.
  • the ion channel modulating compounds described herein may provide pharmaceutically acceptable formulations with therapeutically effective amounts of one or more of ion channel modulating compounds, formulated with one or more pharmaceutically acceptable carriers (additives), other active agents, and/or diluents.
  • Formulations of ion channel modulating compounds may be for administration in solid, liquid, vapor, or suspension form, including those adapted for oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, polymer release formulations, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; topical application, for example, as a cream, ointment or spray applied to the skin; or intravaginally or intrarectally, for example, as a pessary, suppository, cream or foam.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, polymer release formulations, pastes for application to the tongue
  • parenteral administration for example, by subcutaneous, intramuscular or intravenous injection as, for example
  • Ion channel modulating compounds as described herein may be formulated for administration with any biologically acceptable medium, including but not limited to water, buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like) or suitable mixtares thereof.
  • the optimum concentration of the ion channel modulating compound in the chosen medium can be determined empirically, according to procedures well known in the art.
  • biologically acceptable medium includes any and all solvents, dispersion media, and the like which may be appropriate for the desired route of administration of the pharmaceutical preparation.
  • Formulations may contain suitable physiologically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the ion channel modulating compounds into preparations which can be used pharmaceutically.
  • Formulations of the ion channel modulating compounds may also include agents which increase or otherwise affect the bioavailability of the drug.
  • bioavailability refers to the effect, availability and persistence of the ion channel modulating compound after being administered to a subject.
  • Pharmaceutically acceptable carriers can be any pharmaceutically acceptable material, composition, or vehicle, including but not limited to a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agonists to an organ, or portion of the body. Each carrier must be compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically acceptable carriers include but are not limited to sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter, waxes, animal and vegetable fats, paraffins, silicones, bentonites, silicic acid, zinc oxide; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-
  • the ion channel modulating compound may be capable of forming pharmaceutically acceptable salts such as inorganic and organic acid or base addition salts of the ion channel modulating compounds described herein. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). In particular, HCl salts of the ion channel modulating compounds may be used.
  • salt forms include hydrochloride, hydrobromide, hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, L- tartrate, citrate, gluconate, benzenesulphonate (besylate), p-toluenesulphonate (tosylate), methanesulphonate (mesylate), esylate, succinate, salicylate, nitrate, sulfate, etc.
  • Formulations of the ion channel modulating compounds can also include wetting agents; emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating agents; sweetening, flavoring, and/or perfuming agents; preservatives; and antioxidants.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate
  • coloring agents such as sodium lauryl sulfate and magnesium stearate
  • coloring agents such as sodium lauryl sulfate and magnesium stearate
  • coloring agents such as sodium lauryl sulfate and magnesium stearate
  • coloring agents such as sodium lauryl sulfate and magnesium stearate
  • coloring agents such as sodium lauryl sulfate and magnesium stearate
  • release agents such as sodium lauryl sulfate and magnesium stearate
  • coating agents such as sweetening, flavoring, and/or perfuming agents
  • antioxidants include but are not limited to water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Fo ⁇ nulations of ion channel modulating compounds may also inco ⁇ orate buffering agents and/or salts to aid abso ⁇ tion or stabilize the ion channel modulating compound.
  • Other additives such as chelating agents, enzymatic inhibitors, and the like, which would facilitate the biological activity of the pharmaceutical composition may also be inco ⁇ orated in the formulation.
  • Formulations of ion channel modulating compounds may also contain opacifying agents.
  • the formulations of ion channel modulating compounds maybe presented in unit dosage form and may be prepared by any methods known in the art.
  • the amount of ion channel modulating compound that can be combined with a carrier material to produce a single dosage form may vary.
  • the amount of ion channel modulating compound in a given formulation may depend upon the host being treated and/or the particular mode of administration.
  • the amount of ion channel modulating compound which can be combined with a carrier to produce a single dosage form will generally be that amount of the ion channel modulating compound which produces a therapeutic effect.
  • Methods of preparing these formulations include the step of bringing into association an ion channel modulating compound with the carrier and/or one or more accessory ingredients. Some formulations may be prepared by bringing an ion channel modulating compound in association with liquid carriers, finely divided solid earners, or both, and then shaping the product.
  • Formulations of the ion channel modulating compound suitable for oral administration maybe in the form of a solid (capsules, cachets, pills, tablets, lozenges, powders, dragees, granules); or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia); andor as mouth rinses or washes and the like; or as a bolus, electuary or paste.
  • a solid capsules, cachets, pills, tablets, lozenges, powders, dragees, granules
  • a solution or a suspension in an aqueous or non-aqueous liquid or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or
  • Solid formulations of ion channel modifying compounds may have pharmaceutically acceptable carriers and extenders including but not limited to sodium citrate or dicalcium phosphate; starches; lactose; sucrose; glucose; mannitol; and/or silicic acid.
  • Solid formulations of the ion channel modulating compound can include additional components including but not limited to binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl py ⁇ olidone, sucrose andor acacia; humectants such as glycerol; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents such as paraffin; abso ⁇ tion accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; lubricants such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents.
  • binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl py ⁇ olidon
  • the formulation may also include buffering agents, particularly when the ion channel modulating compound is in the form of a capsule, tablet or pill.
  • Solid formulations may also include fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Solid formulations such as pills and tablets may be formed by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixtare of powdered ion channel modulating compound moistened with an inert liquid diluent.
  • Solid formulations of ion channel modulating compounds described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings.
  • Solid dosage forms may also be formulated so as to provide slow or controlled release of the ion channel modulating compound.
  • solid formulations could include any material that could provide a desired release profile of the ion channel modulating compound, including but not limited to hydroxypropylmethyl cellulose in varying proportions, or other polymer matrices, liposomes and/or microspheres.
  • Formulations of ion channel modulating compounds may also be formulated to release the ion channel modulating compound only, or preferentially, in a certain portion of the gastrointestinal tract, for example, by including an embedding agent.
  • embedding agents which can be used include but are not limited to polymeric substances and waxes.
  • the ion channel modulating compound may also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • Coated or encapsulating formulations of ion channel modulating compounds may also be formulated to deliver pulsatile, sustained, or extended release.
  • one method of pulsatile release could be achieved by layering multiple coatings of ion channel modulating compound, or by inco ⁇ orating the ion channel modulating compound within different regions of the formulation having different release times.
  • Liquid dosage formulations for oral administration of the ion channel modulating compounds may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage formulations may contain inert diluents commonly used in the art, including but not limited to water or other solvents; solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol; oils (in particular, cottonseed, groundnut, co , germ, olive, castor and sesame oils); glycerol; tetrahydrofuryl alcohol; polyethylene glycols; and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, including but not limited to water or other solvents; solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • the ion channel modulating compound may also be formulated as a suspension.
  • Suspensions of the ion channel modulating compound may include suspending agents.
  • suspending agents include but are not limited to ethoxylated isostearyl alcohols; polyoxyethylene sorbitol and sorbitan esters; microcrystalline cellulose; aluminum metahydroxide; bentonite; agar-agar; tragacanth; and mixtures thereof.
  • Formulations of the ion channel modulating compound for rectal or vaginal administration may be presented as a suppository.
  • Suppository formulations may be prepared by mixing one or more ion channel modulating compounds with one or more suitable nonirritating excipients or carriers.
  • suitable ca ⁇ iers include any compound which is solid at room temperature but liquid at body temperature, and therefore will melt in the rectum or vaginal cavity and release the ion channel modulating compound. Examples of such carriers include but are not limited to cocoa butter; polyethylene glycol; a suppository wax or a salicylate.
  • Formulations of the ion channel modulating compound suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art.
  • Formulations of the ion channel modulating compound suitable for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the ion channel modulating compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • Powders and sprays may contain, in addition to an ion channel modulating compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the ion channel modulating compound may also be formulated as a transdermal patch.
  • Transdermal patches have the added advantage of providing controlled delivery of the ion channel modulating compound into the body.
  • Such formulations may be made by dissolving or dispersing the ion channel modulating compound in the proper medium.
  • Abso ⁇ tion enhancers may also be used to increase the flux of the compound across the skin.
  • the rate of flux maybe controlled. Examples of ways of controlling the rate of flux include but are not limited to rate controlling membranes or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations of the ion channel modulating compound include, but are not limited to, eye ointments, powders, solutions and the like.
  • Formulations of ion channel modulating compounds for parenteral administration may have one or more ion channel modulating compound in combination with one or more pharmaceutically acceptable isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use.
  • Parenteral formulations may contain antioxidants; • buffers or solutes which render the formulation isotonic with the blood of the intended subject; bacteriostats; suspending; or thickening agents.
  • Injectable depot formulations of the ion channel modulating compound can be made by forming microencapsulated matrices of the ion channel modulating compounds in biodegradable polymers.
  • biodegradable polymers include, but are not limited to polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides).
  • the ratio of ion channel modulating compound to polymer and the nature of the particular polymer employed can affect the rate of ion channel modulating compound released.
  • Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions.
  • Formulations of the ion channel modulating compounds may also include anti- contamination agents for the prevention of microorganism contamination.
  • Anti- contamination agents may include but are not limited to antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • Formulations of the ion channel modulating compound may also be sterilized by, for example, by filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid formulations which can be dissolved in sterile water, or some other sterile medium immediately before use or formulation.
  • Formulations of the ion channel modulating compounds may also include isotonic agents such as sugars, sodium chloride, and the like.
  • the ion channel modulating compound In some cases it is desirable to prolong the effect of the ion channel modulating compound. This may be accomplished in formulations of the ion channel modulating compound that slow the abso ⁇ tion of the ion channel modulating compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material having poor water solubility. The rate of abso ⁇ tion of the ion channel modulating compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed abso ⁇ tion of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle. Prolonged abso ⁇ tion formulations for injection can include agents which delay abso ⁇ tion including but not limited to aluminum monostearate and gelatin.
  • Ion channel modulating compounds can be given per se or as formulations containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of ion channel modulating compound.
  • the ion channel modulating compounds described herein may be formulated as immediate release (ER) or controlled release (CR) tablets.
  • the ion channel modulating compound formulation contains (1R,2R)-
  • Both ER and CR forms of the drug may be formulated so that a final dosage form exhibits many desirable properties including, but not limited to: good tabletting characteristics (e.g., good flow, compression, appearance, weight variation, hardness, friability, content uniformity and dissolution rate properties), good bioavailability profiles (e.g., 12-hour in-vivo drug release profile for the CR tablet), excellent stress and long-term stability, satisfies USP and EU standards, small tablet size, simple but efficient and cost- effective processing, and CR and ER tablets may have approximately the same weight and appearance.
  • good tabletting characteristics e.g., good flow, compression, appearance, weight variation, hardness, friability, content uniformity and dissolution rate properties
  • bioavailability profiles e.g., 12-hour in-vivo drug release profile for the CR tablet
  • excellent stress and long-term stability satisfies USP and EU standards
  • small tablet size simple but efficient and cost- effective processing
  • CR and ER tablets may have approximately the same weight and appearance
  • CR tablets may be made by inco ⁇ orating the drug within a matrix systems, including but not limited to: a hydrophilic matrix system, a hydrophobic (plastic matrix system), a hydrophilic/hydrophobic matrix system, a fat/wax system, and a film-coated particulate system.
  • a matrix systems including but not limited to: a hydrophilic matrix system, a hydrophobic (plastic matrix system), a hydrophilic/hydrophobic matrix system, a fat/wax system, and a film-coated particulate system.
  • Hydrophilic matrix systems show uniform and constant drug diffusion from a tablet prepared with a hydrophilic, gelling excipient after it is placed in an aqueous environment. Drug release is controlled by a gel diffusional barrier which is formed. The process is usually a combination of gel hydration, drug diffusion, and gel erosion.
  • Hydrophobic (plastic) matrix systems utilize inert, insoluble polymers and copolymers to form a porous skeletal structure in which the drug is embedded. Controlled drug release is effected by diffusion of drug through the capillary wetting channels and pores of the matrix, and by erosion of the matrix itself.
  • Hydrophilic/ hydrophobic matrix systems utilize a combination of hydrophilic and hydrophobic polymers that forms a soluble/insoluble matrix in which the drug is embedded. Drug release is by pore and gel diffusion as well as tablet matrix erosion. The hydrophilic polymer is expected to delay the rate of gel diffusion.
  • the drug is inco ⁇ orated in a hot melt of a fat-wax matrix, solidified sized and compressed with appropriate tablet ingredients. Controlled release of the drug is effected by pore diffusion and erosion of the fat-wax matrix. The addition of a surfactant as a wicking agent helps water penetration of the matrix to cause erosion.
  • Film-coated particulate systems include time-release granulations, prepared by extrusion- spheronization process or by conventional granulation process that have been film-coated to produce differing species of controlled release particles with specific drug release characteristics.
  • Controlled release particles may be compressed together with appropriate tabletting excipients to produce tablets with the desired controlled release profile.
  • Drug release is by particle erosion in either acid (gastric) or alkaline (intestinal) pH.
  • CR formulations of the drag may be processed by methods including but not limited to: direct compression (dry blend of drug with flowable excipients followed by compression), wet granulation (application of a binder solution to powder blend, followed by drying, sizing, blending and compression), dry granulation or compaction (densifying the drug or drug/powder blend through slugging or with a compactor to obtain flowable, compressible granules), fat-wax mot melt granulation (embedding of drug in molten fatty alcohols, followed by cooling, sizing, blending and compression), and film-coating of particulates (dry blend, wet granulation, kneading, extrusion, spheronization, drying, film-coating, followed by blending of differing; species of film-coated spheres, and compression).
  • direct compression dry blend of drug with flowable excipients followed by compression
  • wet granulation application of a binder solution to powder blend, followed by drying
  • a 100 mg CR formulation containing fillers, a glidant, lubricants and a hydrophilic polymer is made by direct compression.
  • the drug is mixed with Starch 1500 in a small polyethylene (PE) bag then passed through a # 30 mesh screen.
  • the screened mix is then transferred to its original PE bag along with Prosolv SMCC90, Lactose Fast Flo and Methoeel K4M and mixed for 2 minutes.
  • a portion (e.g. Ig) of this blend is then mixed with Magnesium Stearate and Stearic Acid in a PE bag, transfe ⁇ ed back to the bulk blend via a #30 mesh screen and blended for 1 minute.
  • Tablets may be compressed with a suitable punch (e.g., a 9 mm punch) on a single punch press to obtain a tablet hardness of 7-12 KN.
  • a suitable punch e.g., a 9 mm punch
  • compositions of alternative formulations of CR tablets such as the hydrophobic and hot melt (solid dispersion) formulations are shown in the table below.
  • the hydrophilic composition is also shown for comparison.
  • IR tablets of the drug may be formulated by compounding the drug with appropriate, fillers, binders, glidants, disintegrants and lubricants that give a satisfactory tabletting characteristics and subsequent rapid disintegration and dissolution of the tablets. Excipients useful for ER tabletting are listed in the following table. Outlined are the chemical and brand names, compendial status, function, and range of use levels:
  • IR tablets of the drug may be made by: direct compression (dry blend of drug with flowable excipients followed by compression), wet granulation (application of a binder solution to powder blend, followed by drying, sizing, blending and compression), dry granulation or compaction (densifying API of API/powder blend through slugging or with a compactor to obtain flowable, compressible granules), or a combination of these steps.
  • Granules of the drug are sized, blended with the appropriate excipients and compressed in tablets.
  • a 100 mg ER formulation containing basic ER excipients i.e., fillers, a glidant, a disintegrant and lubricants may be made by direct compression.
  • This formulation is blended in small PE bags and subsequently compressed manually on a single punch bench tablet press with an appropriate tablet punch.
  • the ion channel modulating drug is mixed with Starch 1500 in a small polyethylene (PE) bag then passed through a # 30 mesh screen.
  • the screened mix is then transfe ⁇ ed to its original PE bag along with Prosolv SMCC90, Lactose Fast Flo and Explotab and mixed for 2 minutes.
  • a portion e.g.
  • the release profile of active agent (such as the ion channel modulating compound) and any additives may be empirically determined in vitro by examining the dissolution of the tablet over time.
  • a USP approved method for dissolution or release test can be used to measure the rate of release in vitro (USP 24; NF 19 (2000) pp. 1941-1951).
  • a weighed tablet of the drug e.g.
  • various ER and CR tabletted formulations of (lR,2R)-2-[(3R)- Hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride may have in vivo cumulative percentage release profiles the same as or substantially the same as shown in Figures 2 and 3.
  • Figure 2 shows that release profile (percent cumulative release over time) for the ER formulation of the ion channel modulating compound.
  • This ER formulation is described in Table 10, Part I below. More than 80% of the drug in the ER form has dissolved by fifteen minutes.
  • the ion channel modulating compounds herein may also be used in conjunction or combination with biomedical devices, including but not limited to applying the ion channel modulating compound as a component of a biomedical device, such as coating the ion channel modulating compound on a device to achieve an extended, immediate, or controlled release; administering the ion channel modulating compound in coordination with a treatment such as administering pre- or post-operatively to a subject; or releasing the ion channel modulating compound from a biomedical device as needed, such as release from a "smart" pacemaker or cardiac sensor.
  • Rechargeable or biodegradable devices could deliver controlled release of the ion channel modulating compounds to a subject.
  • Such devices include but are not limited to slow release polymeric devices for the controlled delivery of drugs, for example proteinaceous biopharmaceuticals; and osmotic pumps and osmotic tables.
  • a variety of biocompatible polymers including hydrogels), including both biodegradable and non-degradable polymers, could form an implant for the sustained release of the ion channel modulating compound at a particular site, including a target site.
  • An implantable or external pump system could also be used to deliver ion channel modulating compounds.
  • Ion channel modulating compounds could also be delivered via incorporation as a coating onto a biomedical device, such as an implantable device (e.g. a heart valve).
  • Implantable systems inco ⁇ orating the ion channel modulating system could be implanted in a subject anywhere that would allow beneficial therapeutic effect, including but not limited to implantation in heart tissue or pericardial sacs.
  • Biomedical devices appropriate for use in conjunction with the ion channel modulating compounds described here could be used to treat or prevent cardiovascular disorders.
  • formulations of the ion channel modulating compounds could be used in combination or conjunction with angioplastic balloons, cardiac monitors, stents (including drug eluting stents), def ⁇ brillators, catheters and heart valves, vascular grafts, pacemaker leads, guide wires, and the like which are placed into the blood vessels or the heart or nearby tissue for purposes of monitoring or repair.
  • On-demand release forms incorporating an ion channel modulating compound can be used for controlled release.
  • Hybrid devices delivering an ion channel modulating compound could incorporate release based on sensing concentration of drug, a biological marker (e.g. enzyme level), or physiological need, h one embodiment, sensing devices could be pacemakers and/or implantable defibrillators modified to release drug upon demand. Drug release could also be regulated and/or monitored by computer control.
  • Example 1 Termination of atrial fibrillation - Step dosing IV study in human subjects [0297] A prospective double-blind, placebo-controlled, randomized, dose-response trial was conducted. The compound used in these studies is (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l- (3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride, which has structural formula
  • Patients were excluded for the following reasons: female patients of child-bearing potential; weight >300 lb; history of long QT syndrome, torsade de pointes or an unco ⁇ ected QT interval of >450 ms; QRS > 120 ms; myocardial infarction, symptoms of angina, congestive heart failure, or stroke within the previous 3 months; cardiac surgery in the previous 6 months; bradycardia ( ⁇ 50 bpm) or sick sinus syndrome unless controlled by a pacemaker; digoxin toxicity; or other reversible cause of atrial fibrillation (such as hyperthyroidism, pulmonary embolism, alcohol intoxication, acute pericarditis); Wolff- Parkinson- hite syndrome; COPD requiring daily-bronchodilation therapy; cyanotic or other significant congenital heart disease; concu ⁇ ent treatment with known QT prolonging drugs or class I or ED anti-a ⁇ hythmic agents (unless the medication was discontinued more than five half-lives before enrollment); oral amio
  • ECGs were interpreted by individual investigators and independently verified by a core lab cardiologist blinded to study treatment.
  • Venous blood samples were drawn for (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride plasma concentrations at 0, 15, 30, 120, 240, 480 minutes, discharge and at atrial fibrillation termination or significant adverse events.
  • the infusion was discontinued if the a ⁇ hythmia terminated after 1 minute of verification, systolic blood pressure decreased to ⁇ 85 mm Hg or increased > 190 mm Hg, HR ⁇ 50 bpm, intolerable side effects or any change in rhythm or atrioventricular conduction occu ⁇ ed that in the investigator's opinion was a threat to patient safety, a new bundle-branch block developed, QRS increased >50%, unco ⁇ ected QT increased to 550 ms or > 25% of baseline or any polymorphic VT was noted. If atrial fibrillation persisted past 1 hour after the last infusion, pacing or electrical cardioversion was permitted.
  • the sample size was based on estimates of a placebo conversion rate of 35%, (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride conversion rate of 60%, an alpha of 0.05 and a beta- of 0.9.
  • a priori up to 20 patients were to be recruited in each group to detect this difference, with an anticipated need of at least 18 evaluable patients per group.
  • the treatment allocation was as follows: placebo/placebo, 20; 0.5 mg/kg + 1.0 mg/kg (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride, 18; and 2.0 mg kg + 3.0 mg (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride, 18.
  • the mean age of the patients was 61 years (range 24-88 years), 61% were male.
  • the average duration of the a ⁇ hythmia was 17.8 ⁇ 13 hours in the placebo group, 23.6 ⁇ 22 hours and 24.7 ⁇ 20 hours in the RSD-1 and RSD-2 dosing groups, respectively.
  • Baseline clinical characteristics were similar across groups except that patients in the placebo group tended to more frequently report atrial fibrillation in the past than in the (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride dosed groups.
  • Adverse Events A total of 39 patients experienced 122 adverse events (AEs) over the course of the study, with a similar incidence of AEs among the three treatment groups. The majority of AEs were of grade 1 (mild) or grade 2 (moderate) intensity. There were 4 AEs that occu ⁇ ed in 2 patients considered either definitely or probably related to study drug. Both patients were in the RSD-2 dose group: one patient reported paraesthesia, and one patient reported paraesthesia, nausea, and hypotension all of mild intensity.
  • cardiac disorders in the placebo group included two patients with ventricular tachycardia and a patient with ventricular extrasystoles. Ventricular extrasystoles were also seen in two patients and sinus bradycardia in one patient of the low dose group. Ventricular extrasystoles were seen in two patients and sinus bradycardia in another patient in the RSD-2 group.
  • Serious AEs Serious AEs were reported in 5 patients (4 patients of the Placebo group and 1 patient of the RSD-1 group). There were no SAEs that were considered related to study drug, and all SAEs resolved either during the course of the study or during the follow-up period. There were no instances of polymorphic ventricular tachycardia in the study.
  • a transient cerebral ischemic attack occu ⁇ ed 1 day after conversion in a placebo treated patient with a therapeutic INR at the time of conversion.
  • the remaining serious AEs in the placebo group consisted of severe bradycardia and hypotension immediately following conversion in one patient, pulmonary edema in another patient and recu ⁇ ent atrial fibrillation in the final patient with a serious AE.
  • One patient in the RSD-1 group experienced VF induced by an asynchronous discharge during an electrical cardioversion attempt performed 1 hour after the second infusion.
  • the cumulative atrial fibrillation termination within 30 minutes of infusion was 61.1% (11 of 18 patients) after 2 + 3 mg/kg (IR, 2R)-2-[(3R)-hydroxypyrrolidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride infusion (the "RSO-2" group), 11.1% (2 of 18 patients) after 0.5 + 1 mg/kg (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride (the "RSD-1 group”) and 5.3% (1 of 19 patients) after placebo + placebo.
  • the median time to termination of atrial fibrillation was 11 minutes after start of the first infusion (range, 3 to 58 minutes) in the RSD-2 group. In fact, all the responders in this group reached primary end-point during drug infusion or within 10 minutes of the last infusion. One of the 11 responders in this group terminated AF, but went into atrial flutter and subsequently converted to NSR 14.5 hours later.
  • (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride rapidly converted atrial fibrillation patients, often during the infusion phase. There were no serious adverse events associated with (IR, 2R)-2-[(3R)- hydroxypy ⁇ olidinyl]- 1 -(3 ,4-dimethoxyphenethoxy)cyclohexane monohydrochloride at plasma levels up to 8.6 ⁇ g/ml, and observed SAEs were more common in the placebo group.
  • Example 2 Pharmacokinetic evaluation of oral dosing in human subjects.
  • This prospective, randomized, placebo-controlled, double-blind, ascending dose stady was conducted to assess safety and oral absorption of (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]- l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride in healthy volunteers.
  • Safety and tolerance were monitored through 12-lead ECG, Holter and telemetry recordings and monitoring of clinical observations, vital signs, clinical chemistries and haematology.
  • Tlie pharmacokinetics was assessed through measurement of (IR, 2R)-2-[(3R)- hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride levels in both urine and plasma.
  • the C ma ⁇ hi fasted volunteers was 1.8 ⁇ 0.4 ⁇ g/ml after the 5 mg/kg p.o. dose and 1.9 ⁇ 0.5 ⁇ g/ml after the 7.5 mg/kg p.o. dose, hi fed volunteers, the Cm ax was 1.3 ⁇ 0.7 ⁇ g/ml after the 5 mg/kg p.o. dose.
  • T max time to maximum plasma levels
  • F% bioavailability
  • the oral bioavailability in the three dosing groups were found to be 71 + 21% (mean + s.d.), 69 + 50% and 58 ⁇ 19%, for 5 mg/kg fasted, 5 m/kg fed and 7.5 mg/kg fasted respectively, indicating that (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride is rapidly and extensively absorbed after oral administration.
  • This study was a prospective, randomized, placebo-controlled, double-blind, ascending dose bioavailability stady of an orally administered aqueous formulation of (IR, 2R)-2-[(3R)-hydroxy ⁇ y ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride in healthy volunteers. Pharmacokinetic assessment and safety monitoring endpoints were evaluated. All doses were administered as a single oral dosing solution.
  • the stady was a prospective, randomized, placebo-controlled, double-blind ascending single-dose dose assessment of the oral bioavailability of (IR, 2R)-2-[(3R)- hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride.
  • Dose - ranging covered two doses (5.0 and 7.5 mg/kg) and involved 24 volunteers. The study was conducted in 3 dosing blocks.
  • the first 8 subjects were fasted from midnight prior to dosing until four hours post-dose.
  • a standard breakfast was administered concomitant with dosing.
  • Inclusion Criteria Females and males aged 18 between 60 years. Females must be non-pregnant and surgically sterile or free of menses for more than two years. If free of menses females must be using an effective form of birth control during the study (from pre-screening) until three months after the follow-up visit. Methods of birth control considered to be effective would include hormonal contraception (the pill), an intrauterine device (ECJD), condoms in combination with a spermicidal cream, total abstinence or sterilization. Males will be advised to refrain from unprotected
  • Exclusion Criteria a) 90 mmHg > systolic blood pressure > 160 mmHg, or, 65 mm Hg > diastolic pressure > 95 mmHg. These will be measured 3 times after sitting for 3 minutes and averaged to determine a baseline BP. b) 50 bpm ⁇ pulse rate >90 bpm. c) PR > 0.21 sec, QRS > 0.11 sec, QT C B > 0. 430 sec for men and QT C B > 0.450 sec for women. d) Participation in any other investigational drug stady within 60 days preceding the start of the stady, or participation in more than 3 other drug studies (for men) / more than 2 other drug studies (for women) in the past 10 months.
  • Dosing was to be terminated if any volunteer that exhibited any significant clinical signs (e.g. tremors) or if the following limits were reached: PR > 0.24 s; QTcB > 0.500s; Pulse Rate ⁇ 40 bpm; Systolic BP ⁇ 80 mm Hg (confirmed by three measurements over three minutes); Evidence of bundle branch block or other serious conduction disturbance.
  • the subject population included men (63%) and women in the age range of 18 — 60 years. Subject body weight ranged from 59.1 to 89.3 kg. Subjects meeting entry criteria and signing informed consent forms were enrolled in the study. Each subject was assessed clinically pre-dose and underwent clinical and pharmacokinetic evaluation during and after dosing. Each subject enrolled in the study was characterized for cytochrome P450 2D6 expression by genotyping using a blood sample.
  • the stady drug was administered in a volume of 150 mL by oral administration. If drug/placebo was administered to fed subjects, then drug/placebo was administered to subjects with a standard breakfast. Subjects remained sitting during drug administration and it was encouraged that they remained sitting for approximately 4 hours post-dose. Telemetry monitoring was conducted from baseline until at least 4 hours post-dose. Vital signs measurements including pulse rate, respiration rate, blood pressure and oxygen saturation were taken at the following timepoints: screening; admission; pre-dose; immediately following dosing; 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug/placebo administration; at follow-up visit; and in the event of an SAE (none occu ⁇ ed).
  • 12-lead ECGs were recorded at the following timepoints: screening; admission; pre-dose; immediately following dosing; 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after drug/placebo administration; at follow-up visit; and in the event of an SAE (none occu ⁇ ed).
  • ECG's were interpreted by a board-certified cardiologist selected by the Sponsor.
  • Baseline and screening 12-lead ECGs were recorded three times consecutively after subject had been sitting for 10 minutes. The ECG recording with the median of the three QTcB interval measurements was used as the ECG for that timepoint.
  • Blood (5 mL) for pharmacokinetic analysis were drawn at the following timepoints via venipuncture or sampling cannula into lithium heparin tabes: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after drug/placebo administration and in the event of an SAE (none occu ⁇ ed).
  • Pharmacokinetic (PK) parameters for each subject were calculated using WinNonlin (Pharsight Corp., Palo Alto, California, USA). A non-compartmental model was used to calculate parameter estimates.
  • the oral bioavailability of (IR, 2R)-2-[(3R)- hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride was calculated using the area under the curves (AUCs) after oral administration compared to the AUCs obtained after iv administration in a previously completed stady (Phase I trial report).
  • Urine was collected each time the subject voided. After dosing specimens were collected over the periods; 0-4 hours, 4-8 hours and 8 hours - discharge.
  • the C max in fasted subjects was 1.8 ⁇ 0.4 ⁇ g/ml after the 5 mg/kg p.o. dose and 1.3 ⁇ 0.7 ⁇ g/ml after the 5 mg/kg p.o. dose in fed subjects .
  • the C max in fasted subjects was 1.9 ⁇ 0.5 ⁇ g/ml after the 7.5 mg/kg p.o. dose;
  • Tmax time to maximum plasma levels
  • F% bioavailability
  • the oral bioavailability in the three dosing groups were found to be 71 ⁇ 21% (mean ⁇ s.d.), 69 ⁇ 50% and 58 ⁇ 19%, for 5 mg/kg fasted, 5 m/kg fed and 7.5 mg/kg fasted respectively, indicating that (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride is rapidly and extensively absorbed after oral administration.
  • Example 3 Pharmacokinetic evaluation of(lR, 2R)-2-[(3R)-hydrox pyrrolidinyl]-l- (3, 4-dimethoxyphenethoxy) cyclohexane monohydrochloride in dogs.
  • the pharmacokinetics of (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride in beagle dogs after dosing via oral gavage, intraduodenally (ED) and intracolonically (IC) was investigated. Pharmacokinetic parameters such as AUC o-t, C ma ⁇ and T ma were determined.
  • Figures 7-10 contain graphical representations of the plasma concentration versus time curves for (IR, 2R)-2-[(3R)-hydroxypy ⁇ olidinyl]-l-(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride in dog.
  • Example 4 Pharmacokinetics of and ion channel modulating compound following single oral administration to male beagle dogs after 7 days of 4 daily doses
  • the pu ⁇ ose of this stady was to investigate the pharmacokinetics of DRUG injection following single oral administration to male beagle dogs after 7 days of 4 daily doses.
  • the ion channel modulating compound applied was (lR,2R)-2-[(3R)- Hydroxypy ⁇ olidinyl]-l-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride (C 2 oH 3 ⁇ NO 4 .HCl) (referred to as "drug" in this example).
  • This drug was prepared and diluted according to protocol specifications as follows:
  • Group 1 DRUG injection solution (10 mL) was diluted with 30 mL of sterile water at a target concentration of 5 mg mL.
  • Group 1 DRUG injection solution (120 mL) was diluted with Study Days 360 mL of sterile water at a target concentration of 5 mg/mL. Study Day 5 6 g
  • Group 2 DRUG injection solution (198 mL) was diluted with 198 mL of sterile water at a target concentration of 10 mg mL.
  • Group 1 DRUG injection solution (11.75 mL) was diluted with 35.25 mL of sterile water at a target concentration of 5 mg/mL.
  • Study Day 8 Study Day 9 Group 2: DRUG injection solution (20 mL) was diluted with 20 mL of sterile water at a target concentration of 10 mg/mL.
  • Dose formulation samples (0.1 mL) were collected from each formulation prior to dosing on Stady Days -1, 1, 4, and 8. Dose formulation samples (0.1 mL) were also collected from each formulation following the first dose of each day (Study Days 1, 2, 5, 7, and 8). Samples were used to verify the concentration of the dose applied.
  • Six male beagle dogs were selected from non-naive animals. The animals were assigned to the study based on acceptable health as determined by the attending veterinarian following a pre-stady health evaluation. The pre-study health evaluation included a physical exam, serum chemistry and hematology evaluations. The animals were placed into two groups of 3 animals per group. Study animals were fasted overnight prior to dosing for Stady Days 1 and 9 only, and food was returned approximately 4 hours post-dose. Fasting was not required on Study Days 2-8 (multiple dosing days).
  • Group 1 animals received a single dose of prepared drug via oral gavage at a target dose level of 5 mg/kg and at a dose volume of 1 mL/kg.
  • Group 2 animals received a single dose of prepared drug via oral gavage at a target dose level of 10 mgkg and at a dose volume of 1 mL/kg.
  • Group 1 and 2 animals received prepared drug 4 times daily (every 6 hours).
  • the gavage tube was flushed with approximately 10 mL of water prior to removal. Dosing proceeded according to protocol and without incident with the following exceptions:
  • This example describes a simulation of the pharmacokinetics of an ion channel modulating compound, particularly the pharmacokinetics of different multiple dosing regimes. This simulation is based on parameters extracted from experimental data defining the plasma levels of one example of an ion channel modulating compound as described herein.
  • the pharmacokinetics of a single oral (bolus) dose of 100 mg of the drug (approximately 10 mg/kg) may be calculated.
  • Figure 15 shows a simulation of this single oral dose. Because the data shown is simulated, the pharmacokinetic profile at any time following administration (t) may be determined. Simulation of this data was performed using known methods.
  • FIG. 16 shows the blood plasma concentration (C p in ⁇ g/ml) for eight doses of 100 mg of drug administered every 2 hours.
  • the steady-state trough (C mm ) value is achieved by six hours (360 minutes). This trough value is approximately 0.92 ⁇ g/mL when the drug is given at a dose of 100 mg every 2 hours.
  • dosing regimes may vary, including variations in the amount of drug given per dose, the method of dosing (formulation), and the time between doses.
  • a "loading dose” of 500 mg followed by several "maintenance" doses of 100 mg given every two hours is simulated in Figure 17.
  • the initial peak in blood plasma concentration (C max ) is followed by the saw-tooth pattern as the concentration of the dmg achieves a trough.
  • the trough concentration (C m ⁇ n ) is approximately 0.92 ⁇ g/ml.
  • Figure 18 shows another example in which the loading dose (first dose) is 150 mg, followed by maintenance dose (subsequent doses) of 100 mg.
  • Drug formulation may also have dramatic effect on the pharmacokinetics of ion channel modulating compounds.
  • the release and continuous release formulations described above may be used to simulate plasma levels.
  • the rate constant (dissolution rate constant) for an IR formulation, a 300 mg Hydrophilic formulation, a hydrophobic formulation, and a hot-melt wax formulation were approximated by fitting measured data to a first-order dissolution model. These rate constants are shown in Table 20. As with all of the modeled parameters, approximations of the dissolution rate constants could be made using different methods, such as zero-order kinetics.
  • Figure 19 shows the pharmacokinetics of these fo ⁇ nulations based on these dissolution rate constants for a single dose.
  • a simulation of a multiple-dosing regime using a 300 mg hydrophilic CR tablet is shown in Figure 20 where maintenance doses are given every eight hours.
  • Figure 21 shows the simulated blood plasma concentration for a loading dose of a 300 mg hydrophilic CR tablet followed by 7 doses of 100 mg every eight hours.
  • the simulations of pharmacokinetics described above are intended only to illustrate the methods, formulations and routes of administration described and claimed herein, and are not intended to limit the methods, formulations and routes of administration to any particular theory or embodiment.

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Abstract

L'invention concerne des procédés, des préparations, des schémas posologiques et des voies d'administration pour le traitement ou la prévention d'arythmies, dont le traitement ou la prévention de la fibrillation auriculaire. Dans ces procédés, la maladie ou l'état est traité(e) ou empêché(e) par l'administration à un sujet d'un ou plusieurs composés modulant les canaux ioniques, le ou les composés de modulation de canaux ioniques produisant des taux de plasma spécifiques chez le sujet. Les composés modulant les canaux ioniques peuvent être des composés éther cycloamine, notamment des composés éther cyclohexylamine.
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US7674820B2 (en) 2003-08-07 2010-03-09 Cardiome Pharma Corp. Ion channel modulating activity I
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US7345087B2 (en) 2003-10-31 2008-03-18 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US8058304B2 (en) 2004-04-01 2011-11-15 Cardiome Pharma Corp. Merged ion channel modulating compounds and uses thereof
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US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
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US7977373B2 (en) 2004-04-01 2011-07-12 Cardiome Pharma Corp. Prodrugs of ion channel modulating compounds and uses thereof
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US7569589B2 (en) 2004-07-29 2009-08-04 Merck & Co., Inc. Potassium channel inhibitors
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US8263638B2 (en) * 2004-11-08 2012-09-11 Cardiome Pharma Corp. Dosing regimens for ion channel modulating compounds
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US8692002B2 (en) * 2004-11-18 2014-04-08 Cardiome Pharma Corp. Synthetic process for aminocyclohexyl ether compounds
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EP2468278A1 (fr) * 2007-05-04 2012-06-27 Cardiome Pharma Corp. Formulations orales à libération contrôlée de composés de modulation de canal ionique et procédés associés pour empêcher l'arythmie
EP2462933A1 (fr) * 2007-05-04 2012-06-13 Cardiome Pharma Corp. Formulations orales à libération contrôlée de composés de modulation de canal ionique et procédés associés pour empêcher l'arythmie
WO2009018547A1 (fr) * 2007-08-01 2009-02-05 Cardiome Pharma Corp. Formulations à libération prolongée pour la prévention d'arythmies

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