Note: Descriptions are shown in the official language in which they were submitted.
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TITLE: USES OF ION CHANNEL MODULATING COMPOUNDS
RELATED PATENTS AND PATENT APPLICATIONS
[0001] This patent application claims the priority benefit of the following
patent applications:
United States provisional patent application number 60/467,159, titled
Antiazrhythmic Drugs,
filed May 2, 2003 with attorney docket number SS479-3002400; United~States
provisional
patent application number 60/516,248, titled Aminocyclohexyl ether compounds
and uses
thereof, filed October 31, 2003 with attorney docket number SS479-3000900;
United States
provisional patent application number 601516,486, titled Aminocyclohexyl ether
compounds
and uses thereof, filed October 31, 2003 with attorney docket number SS479-
3000901; United
States provisional patent application number 60/493,392, filed Aug. 7, 2003
with attorney
docket number SS479-3000300; United States provisional patent application
number
60/526,911, filed Dec. 3, 2003 with attorney docket number SS479-3001800;
United States
provisional patent application number 60/527,169, filed Dec. 4, 2003 with
attorney'docket
number SS479-3001801; United States provisional patent application number
60/52$,251,
titled Uses of Antiarrhythmic Compounds, filed December 8, 2003 with attorney
docket
number SS479-3001400; United States provisional patent application number
60/544,941,
titled Mixed Ion Channel Blockade for Therapeutic Use, filed February 13, 2004
with .
attorney docket number SS479-3002000; and United States provisional patent
application
number 60/559,405, titled Formulations and uses of ion channel modulating
compounds, filed
April 1, 2004 with attorney docket number SS479-3001500. The contents of each
of these
patent applications is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] 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
SUBSTITUTE SHEET (RULE 26)
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compounds used to treat or prevent arrhythmia and other diseases, and in
particular atrial
fibrillation, are described.
BACKGROUND
[0003] Cardiac arrhythmias often occur as complications to cardiac diseases
such as
myocardial infarction and heart failure. In serious cases, arrhythmias can
cause sudden death.
[0004] 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 "AF." Currently, the development or exacerbation of AF often
prompts
emergency department (ED) presentations. The incidence of arrhythmias
increases with age,
and with the aging population in developed countries, the prevalence is
expected to rise
substantially over the next several decades. Overall, 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.
[0005] 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 infra-atrial thrombus
formation. Electrical
cardioversion is effective in restoring sinus rhythm but requires procedural
sedation or
anesthesia and is not successful in all cases.
[0006] Currently available converting agents have highly variable efficacy and
several safety
limitations associated with their use. In addition, placebo-controlled trials
that establish the
efficacy and safety of these pharmacological therapies for acute conversion
are limited.
[0007] ~An efficacious, simple, and safe pharmacological alternative to
existing methods of
cardioversion would be a welcome development for patients with arrhythmias and
their
treating physicians.
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SUMMARY
[0008] 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. In these
methods, 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. Also provided are
methods for
providing specified plasma levels of ion channel modulating compounds in a
subject.
[0009] Various subjects to which the ion channel compound or compounds may be
administered 'are described in detail in the Detailed Description section. In
one version of the
methods, the subject is a human subject.
[0010] Various formulations, routes of administration, and dosing regimes that
may
be used are described in detail in the Detailed Description section. In one
version of the
methods, the formulation is an intravenous formulation. In one version of the
methods, the
formulation is an oral formulation. The formulations may include one or more
ion channel
modulating compounds together with other optional components. The formulations
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.
[0011] Regarding the levels of ion channel modulating compounds produced in
the
blood plasma by administration of the ion channel modulating compound or
compounds, the
plasma levels may be characterized using a variety of characterizations,
including (1) that the
characterization that the concentration is above some concentration level for
some amount of
time, (2) that the CmaX 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.
[0012] 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 ~Cg/ml
for at least
some time; (2) has a C~,~ of greater than about 0.1 ~Cg/ml; (3) has a CmaX of
between about 0.3
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,ug/ml and about 20 ,uglml; (4) has a Cm~ of between about 0.3 ~,g/ml arid
about 15 ~,g/ml; (5)
is greater that about 0.1 ~ug/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 ,ug/ml; (9) has a mean trough concentration of less than about 10
,ug/ml; (10) has a
steady state concentration of less than about 10 ~,g/ml; (11) has a mean
trough concentration
of between about 1 ng/ml and about 10 ~,glml; (12) has a mean trough
concentration of
between about 0.3 ~.g/ml and about 10 ~g/ml; (13) has a steady state
concentration of between
about 0.3~,g/ml and about 10 ~,glml; (14) has a mean trough concentration of
between about
0.3~g/ml and about 3 ~.g/ml; (15) has a steady state concentration of between
about 1 ng/ml
and about 10 ~,g/ml; (16) has a steady state concentration of between about
0.3~.glml and
about 3 ~,g/ml. The total ion channel modulating compound concentration may
possess one
or more of these characterizations.
[0013] In the methods of treating arrhythmias, including atrial fibrillation,
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 ,ug/ml
for at least some time; (2) has a CmaX of greater than about 0.1 ~Cglml; (3)
has a CmaX of
between about 0.3 ~.g/ml and about 20 ~,glml; (4) has a Cm~ of between about
0.3 ~Cg/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.
(0014] In the methods of preventing or postponing onset of arrhythmias,
including
atrial fibrillation, 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 ~Cg/ml; (3) has a mean trough concentration of less than
about 10 ~tg/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 ,ag/ml and about 10 ~Cg/ml; (7) has a mean
trough
concentration of between about 0.3 ~.g/ml and about 3 ~,g/ml; (8) has a steady
state
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concentration of between about 0.3 ~Cg/ml and about 3 ~.g/ml. The total ion
channel
modulating compound concentration may possess one or more of these
characterizations.
[0015]
[0016]
(0017]
[0018] Various ion channel modulating compounds that may be used in the
methods
provided in this patent are described in detail in the Detailed Description
section. In one
version the ion channel modulating compound may be a compound of formula
.o
N / RS
[0019] - off
[0020]
(0021] where R4 and RS are independently selected from hydrogen, hydroxy and
C1-C6alkoxy. In one version, the ion channel modulating compound is a
monohydrochloride
salt of the formula
O / OCH3
OCH3
',~N~,~iIOH _HCl
[0022 ~/]
[0023] In one version, the ion channel modulating compound is a
cycloalkylamine
ether compound of formula
A\X- 'O
R~
N
\ R2
[0024] Li
[0025]
[0026] where n =1,2,3, or 4 and the other substituents are as defined in the
Detailed
Description section.
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[0027j For all ion channel modulating compounds described above and elsewhere
in
this patent, isolated enantiomeric, diastereomeric and geometric isomers of
the compounds
may be used and mixtures of the compounds may be used. In addition, solvates
or
pharmaceutically acceptable salts of the compounds may be used.
[0028] Other aspects of the methods provided in this patent are described in
detail in
the Detailed Description section.
BRIEF DESCRIPTION OF THE DRAWINGS
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 (1R, 2R)-2-((3R)-
hydroxypyrrolidinyl]-1-(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 (1R,
2R)-2-((3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane rnonohydrochloride
over
time.
Figure 4 shows the cumulative percentage of patients terminating atrial
fibrillation
(AF) after infusions of placebo, 0.5 and 1 mglkg (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-
(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride or 2.0 and 3.0 mg/kg
(1R, 2R)-
2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride,
in patients with recent onset atrial fibrillation.
Figure 5 shows the plasma concentrations of (1R, 2R)-2-[(3R)-
hydxoxypyrrolidinyl~-
1-(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
mglkg i.v. (filled
circles).
Figure 6 shows (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(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).
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Figure 7 shows individual Plasma Concentration of (1R, 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 (1R, 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 (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
Versus
Time Following Intracolonic Administration in Beagle Dogs.
Figure 10 shows average plasma concentration of (1R, 2R)-2,-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
Versus
time following administration in beagle dogs (N=6), all routes compared.
Figure 11 shows dose normalized AUCs of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-
1-
(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride for each route of
administration
in beagle dogs.
Figure 12 shows the plasma concentration levels of of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
after a
single oral dose in six dog subjects.
Figure 13 shows the plasma concentration levels of of (1R, 2,R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(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 (1R, 2R)-2-
[(3R)-hydroxypyrrolidinyl]-1-(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.
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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.
DETAILED DESCRIPTION
[0029] 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.
[0030] Atrial fibrillation is one type of arrhythmia specificially referred to
throughout this
description. However the methods, formulations and routes of administration
described
herein are not limited to atrial fibrillation, and may be used to treat,
prevent andlor postpone
the onset of any arrhythmia, including but not limited to: ventricular
arrhythmias (e.g.,
ventricular tachycardia, ventricular fibrillation, premature ventricular
contractions),
supraventricular 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. It is also believed that
the
formulations and routes of administration described in this patent may be used
to treat other
diseases, which are described in this Detailed Descr-iptaofi section.
[0031] Generally, the subject in which arrhythmia or other diseases may be
treated or
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prevented is any mammal. In one version the subject is a human subject. In one
version the
subject is any domestic animal, including but not limited to dogs, and cats.
In one version,
the subject is any livestock animal, including but not limited to pigs,
horses, cows and sheep.
In one version, the subject is any zoo animal, including but not limited to:
Bengel tigers,
camels and giraffes.
[0032] In this Detailed Description, we first describe methods for treating
arrhythmia (e.g.
atrial fibrillation) and formulations and routes of administration that may be
used in these
methods. We then describe methods for preventing or postponing onset of
arrhythmia and
formulations and routes of administration that may be used in these methods.
We then
describe useful plasma levels and other diseases that it is believed may be
treated using these
plasma levels. We also 'describe specific compounds and general classes of
compounds, and
general formulations, routes of administration, and dosage forms that may be
used in the
methods described in this patent. We also present examples demonstrating the
methods
described in this patent.
METHODS AND FORMULATIONS FOR TREATING ARRYTHMIA
[0033] In the treatment methods described in this section, 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.
[0034] 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. In the context of
treatment of
arrhythmia, 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.
[0035] In one version, the arrhythmia treated is atrial fibrillation.
[0036] Generally, the subject in which arrhythmia may be treated is any
mammal. In one
version, the subject is a human subject. In other versions the subject is a
domestic animal,
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including but not limited to dogs and cats; or a farm animal, including but
not limited to...
Ion Channel Modulation Compounds That May Be Used In the Methods o Treatin
Arrhytlamia
[0037] Generally, any ion channel modulating compound capable of treating
arrhythmia (e.g.
atrial fibrillation) 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.
(0038] In one version of the methods and formulations described in this
section, the ion
channel modulating compound is (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride.
Fornaulatiotas and Routes o~Adnainistration That May Be Used In the Methods of
Treating Arrla~hmia
(0039) Generally, the formulation used for treating arrhythmia (e.g. atri.al
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.
[0040) Generally, 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. General
formulations, routes of administration, and dosage forms that may be 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 treating arrhythmia using the methods described in this
patent are
described in more detail below in this section.
[0041] In one nonlimiting example, the formulation is an oral dosage
formulation or an
l0
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intravenous dosage formulation. An example of a formulation that may be used
for treating
arrhythmia is an infra-venous 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. A specific example of an
ion channel
modulating compound that may be used is (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-
1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride.
[0042] One specific example of a formulation that may be used to treat
arrhythmia by
intravenous administration is a 20 mglml (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-
1-(3,4-
dirnethoxyphenethoxy) 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.
Amounts of.~oh Channel Modulating Corrapoufads arad Dosih~ Re i~ mes, for
Methods of
Ti~eatin~ A~hythnaia
[0043] Generally, the formulation used for treatment of arrhythmia (e.g.
atrial fibrillation)
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.
[0044] As used in this section, 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.
[0045] The formulation containing the therapeutically effective amount of the
ion channel
modulating compound or compounds may be administered in repeated doses. When
administered as 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.
[0046] In one example for treating a human subject, the formulation is
administered in a dose
delivering between about 0.1 mglkg and about 10 mg/kg of the ion channel
modulating
11
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compound or compounds or compounds to the subject. In another version, 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. As used in this patent,
"mglkg"
means the amount of ion channel modulating compound or compounds per kg body
weight of
the subject. For example, but without limitation, to administer 0.1 mg/kg of
ion channel
modulating compound to a subject of mass 50 kg the administered dose contains
Smg of ion
channel modulating compound or compounds.
[0047] In other versions, the formulation is delivered by repeat dosing where
a first dose
delivers between about 0.1 mglkg and about 10 mg/kg of ion channel modulating
compound
ar compounds and a second dose delivers between about 0.1 mg/kg and about 10
mglkg of
ion channel modulating compound or compounds. These first two doses may
optionally be
followed by one or more subsequent doses. In other versions, 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 delivexs between about 0.5 mglkg and about 10 mg/kg of ion channel
modulating
compound ox compounds; or the first dose delivers between about 1.0 mg/kg and
about 5
mg/kg of ion channel modulating compound ox compounds and the second dose
delivers
between about 1.0 mg/kg and about 5 mg/kg of ion channel modulating compound
or
compounds.
[0048] In the above repeated dosing examples 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. In one example, 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. In one verision repeated doses
of between
about 0.01 mg/kg and about 10 mg/kg are delivered per hour for up to 36 hours.
[0049] Generally, 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. In addition, 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.
12
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Plasma Levels oflon Channel Modulating Compounds in Methods ofTreatin
gArrhythmias
[0050] Generally 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.
[0051] As used in this patent, unless the context makes it clear otherwise,
the blood plasma
level is the concentration of the ion channel modulating compound or compounds
in the
blood plasma of the subject.
[0052] In one example in the treatment of a subject, the blood plasma level of
the ion channel
modulating compound or compounds has a CmaX of at least 0.1 ~g/ml during
and/or following
administration of one or more doses of the formulation.
[0053] In another version, the blood plasma level of the ion channel
modulating compound or
compounds has a Cm~ of between about 0.3 ~glml and about 20 ~,glml during
andlor
following administration of one or more doses. In one version, the blood
plasma level of the
ion channel modulating compound or compounds has a Cmax of between about 0.3
~,g/ml arid
about lS~,g/ml during and/or following administration of one or more doses.
[0054] In one example in the treatment of a subject, the blood plasma levels
of the ion
channel modulating compound or compounds is at least about 1 pg/ml for a time
of about 2
hours during and/or following the administration of the first dose of
formulation. In another
version, the blood plasma level of the ion channel modulating compound or
compounds is at
least about 0.1 ~glml for a time of about 10 hours during and/or following the
administration
of the first dose of the formulation. In one nonlimiting example, these blood
plasma levels
are maintained by administering two or more repeated doses of the specific
intravenous
formulation described above in this section.
METHODS AND FORMULATIONS FOR PREVENTING OR POSTPONTNG ONSET OF
ARRHYTHMIA
[0055] In the prevention or postponement of onset~of arrhythmia methods
described 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. Prevention and postponement of onset include prevention and
postponement of
13
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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.
[0056] As used in this patent, unless the context makes clear otherwise,
"prevention," and
similar word such as "prevented," "preventing" etc, is an approach for
obtaining beneficial or
desired results, including and preferably clinical results. In the context of
prevention of
arrhythmia, 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 fox 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.
[0057] In one version the arrhythmia to be prevented is atrial fibrillation.
[0058] Generally, the subject in which arrhythmia may be prevented or for
which onset may
be postponed is any mammal. In one version, the subject is a human subject. In
one version,
the subject is any domesic animal, including, but not limited to cats, dogs,
etc. In one
version, the subject is any farm animal, inlcluding, but not limited to pigs,
cows, horses, etc..
Ion Channel Modulation Compounds That Ma,~Be Used In Tlae Methods of
Preverztin~ ~r Postponi~~ Onset o Arrla thmia
[0059] Generally, any ion channel modulating compound capable of preventing or
postponing onset of arrhythmia (e.g. atrial fibrillation) may be used in the
methods and
formulations described in this section. Specific ion channel modulating
compounds that may
be used axe 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.
[0060] In one version of the methods and formulations described in this
section, the ion
channel modulating compound is (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride.
Formulations arad Routes ofAdministration That May Be Used In The Methods of
Preventing or mostponing onset ofArrhythmia
14
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[0061] Generally, 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.
[0062] Generally, any formulation, route of administration, and dosage form
capable of being
used in the methods for preventing or postponing onset of arrhythmia described
in this patent
may be used. General formulations, routes of administration, and dosage forms
that may be
used axe 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. In one
nonlimiting example, the formulation is an oral dosage formulation.
[0063] 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
(1R, 2R)-2-
[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride.
[0064] .One specific example of a formulation that may be used to prevent or
postpone onset
arrhythmia by oral administration is a controlled release (CR) formulation,
described below.
Amounts oflon Chanzzel Modulating Conzpounds azzd Dosizz~ Reginzes for Methods
of
Preverztin~or Postpotzing Onset o Arr7a thrnia
[0065] Generally, 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
CA 02524034 2005-11-O1
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arrhythmia in the subject. As used in this section, 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.
[0066] The formulation containing the therapeutically effective amount of the
ion channel
modulating compound or compounds may be administered in repeated doses. When
administered as 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.
[0067] In one example for preventing or postponing onset of arrhythmia in a
human subject,
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. In another version, the formulation is administered in a dose
delivering between
about 0.5 mglkg 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.
(00681 In other versions, 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. In other
versions, 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
arid about 10 mglkg of the ion channel modulating compound or compounds or
compounds;
or the first dose delivers between about 1.0 mglkg 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.
(0069] In the above repeated dosing examples the time between repeated dosing
may
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generally be any time such that the repeated dosing delivers a therapeutically
effective amount
of the ion channel modulating compound or compounds. In one example, the time
between
repeated doses may be 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
horns and 24 hours. In one version the time between doses is about 12 hours.
[0070] Generally, 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. In addition, 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.
Plasma Levels oflon Claannel Modulating Compounds ih Methods ~PYeventif~ OY
postponing onset ofA~~rhytlzmia
[0071] Generally 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):
[0072] In one example in the prevention or postponing onset of arrhythmia in a
subject, the
blood plasma level of the ion channel modulating compound or compounds has a
CmaX of at
least 50 ng/ml following administration of one or more doses of the
formulation. In another
version, the blood plasma level of the ion channel modulating compound or
compounds has a
Cm~ of between about 50 ng/ml and about SO~g/ml following administration of
one or more
doses. In other versions, the blood plasma level of the ion channel modulating
compound or
compounds following administration of one or more doses has a CmaX of between
about 50
nglml and about 30~.g/ml; or between about 50 ng/ml and about 20p,g/ml; or
between about
50 ng/ml and about 10~g/ml; or between about 0.3 gg/ml and about 3 ~,g/ml; or
between
about 1 O~,glml and about 50pg/ml; or between about 20~.g/ml and about
50~g/ml; or between
about 30~,g/ml and about 50~g/ml.
17
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[0073] In one example in the prevention or postponing onset of arrhythmia in a
subject, 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.
[0074] In one example in the prevention or postponing onset of arrhythmia in a
subject, the
blood plasma levels of the ion channel modulating compound or compounds has a
mean
trough value of between about 50 ng/rnl and about 30~g/ml. In another version,
the mean
trough value is between about 50 nglml and about 20wg/ml. In another version,
the mean
trough value is between about 50 ng/ml and about l Opg/ml. In another version,
the mean
trough value is between about 1 ng/ml to 10 ~g/ml. In another version, the
mean trough value
is between about 0.3 ~Cg/ml and about 3 pg/ml. As used herein, unless the
context makes
clear otherwise, 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. For example, but without.limitation, 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.
[0075] In one version of 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. In this situation, 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. Instead, 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. In this
situation, the
ranges of mean trough valves described for the multiple dosing regime is
replaced by ranges
for the steady state concentration. For example, in one version the steady
state concentration
18
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is less than about 20~,g/ml. In another version, the steady state
concentration is less than
about 10 ~Cg/ml. In another version, the steady state concentration is between
1 ng/ml and 10
,ug/ml. In another version, the steady state concentration is between 0.3
~.g/ml and 3 ,ug/ml.
RATES AND MECHANISM FOR ABSORPTION OF ION CHANNEL MODULATING
COMPOUNDS
[0076] In one version of the methods described in this patent, the ion channel
modulating
compound or compounds that are administered to a subject have a rate of
absorption that is
substantially independent of the site or route of administration. In one
version, 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. Ira one
version, 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 colon of the subject. In
one
version, the rate of absorption 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 absorption of the ion channel modulating compound or
compounds
administered to a dog orally is approximately equivalent to the rate of
absorption of the ion
channel modulating compound or compounds administered in the duodenum of the
dog. In
one version, the rate of absorption of the ion channel modulating compound or
compounds
administered to a dog orally is approximately equivalent to the rate of
absorption of the ion
channel modulating compound or compounds administered in the colon of the dog.
[0077] In one version of the ,methods described in this patent, following
administration of the
ion channel modulating compound or compounds to a subject, the blood plasma
level of the
ion channel modulating compound or compounds is substantially independent of
the route of
administration. In one version, 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. In one version, the blood
plasma level of the
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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. In one
version the subject
is a dog.
j0078] As used herein, unless the context makes it clear otherwise, the xate
of absorption 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 absorption of the ion channel modulating compound or compounds is
measuxed 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 absorption of the
ion channel
modulating compound or compounds is measured by the peak blood plasma level
(Cm~) of
the ion channel modulating compound or compounds and the time after
administration that
the peak blood plasma level occurs (Tm~).
j0079] As used in this patent, unless the context makes it clear otherwise, a
second rate of
absorption is substantially equivalent to a first rate of absorption if the
value of the second
rate of absorption is within about twenty percent of the value of the first
rate of absorption, or
within about ten percent of the value of the first rate of absorption, or
within about five
percent of the value of the first rate of absorption. As used in this patent,
unless the context
makes it clear otherwise, 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 fixst 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.
METHODS FOR PRODUCING BLOOD PLASMA LEVELS OF ION CHANNEL
MODULATING COMPOUNDS
j0080] Generally, described in this section are specific useful blood plasma
levels of ion
channel modulating compounds and methods of producing the levels. As described
in the
section above, the blood plasma levels of ion channel modulating compounds may
be used to
treat or prevent arrythmias including atrial fibrillation. However, it is also
believed that the .
blood plasma levels of ion channel modulating compounds may be used to treat
or prevent
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other diseases. Examples of diseases which it is believed may be teated are
described in this
section.
[0081] Useful blood plasma levels in a subject of ion channel modulating
compounds in a
subject include: (1)greater than about 0.1 ~Cg/ml for at least some time;
(2)CmaX greater than
about 0.1 ~Cglml; (3)Cm~ between about 0.3 pg/ml and about 20 pg/ml; (4)CmaX
between about
0.3 ,ug/ml and about 15 ~.g/ml; (5)greater that about 0.1 p,g/ml fox a period
of time of at least
about 10 houxs; (6)greater that about 1.0 pg/ml for a period of time at least
about 2 hours;
(7)mean trough less than about 20 ,ug/ml; (8)steady state concentration less
than about 20
~Cglml; (9)mean trough less than about 10 p,g/ml; (10)steady state
concentration less than
about 10 ,ug/ml; (11)mean trough concentration between about 1 ng/ml and about
10 pg/ml;
(12) mean trough concentration between about 0.3 ,ug/ml and about 10 ~tg/ml;
(13)steady state
concentration between about 0.3,ug/ml and about 10 ,ag/ml; (14)mean trough
concentration
between about 0.3~Cg/ml and about 3 p,g/ml; (15)steady state concentration
between about 1
ng/ml and about 10 ,ug/ml; (16)steady state concentration between about
0.3,ug/ml and about
3 ,ug/ml.
[0082] 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.
[0083] 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.
[0084] Generally, 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 may be used are described in the Formulations,
Routes of
Adnaifaistration and Dosage section. Specific, nonliiniting 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.
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[0085] As shown elsewhere in this patent, the blood plasma levels described in
this section
may be used to treat or prevent arrythmias, including but not limited to
atrial fibrillation. It is
also believed that 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 the 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, irntable bowel syndrome
Crohn's disease,
prostatic hyperplasia, 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, myopathies, Becker's myotonia,
myasthenia gravis,
paramyotonia congentia, malignant hyperthermia, hyperkalemic periodic
paralysis,
Thomsen's myotonia, autoimmune disorders, graft rejection in organ
transplantation or bone
marrow transplantation, alopecia, diseases or dysfunctions of ion channels and
receptors,
diseases of voltage-gated ion channels, paralysis. This list is illustrative
of the kinds of
disorders for which the present invention could be used, and is not intended
to be either
limiting or exhaustive.
[0086] 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.
[0087] For certain of the ion channel modulating compounds described in this
patent
application, 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 andlor prevention of electrical rhythm
disturbances in the
atria without subsequent effects on the electrical activity in the ventricle.
[0088] The methods and ion channel modulating compounds described in this,
patent
application are proposed for use in diseases and conditions including without
limitation the
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management of atrial fibrillation, flutter and other supraventriculax rhythm
disturbance
without adverse effects or substantial adverse effects on the electrical
activity and rhythm of
the ventricles.
[0089] In one version of the methods described in this patent application 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.
[0090] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to treat andlor prevent diseases or
conditions by
modulating the late sodium current. The late sodium current may also be
referred to as the
persistent sodium current. In one version of the methods described in this
patent application
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 one
version of the
methods described in this patent application 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. In one version of the methods
described in
this patent application an ion channel modulating compound is administered to
treat and/or
prevent and/or diagnose congenital myotonia.
[0091] In one version of the methods described in this patent application 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 Ito andlor Ikur.~ In one
embodiment, acute rhythm
disturbances in the heart resulting from slowing conduction (e.g reentrant
arrhythmia under
acute ischemia or other disease state) can be treated or prevented by reducing
risks associated
with alteration in cardiac rhythm. In one method described in this patent
application, a
therapeutically effective amount of a composition effective to treat andlor
prevent and/or
diagnose acute rhythm disturbances in the heart under pathological conditions
is given to a
patient in need thereof.
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[0092] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to treat andlor prevent rhythm disorders
in the
ischemic heart where such rhythm disturbances are mediated by prolonging
refractoriness
mediated by Ik"r and Ito thusly prolonging the voltage time course of
repolarization.
[0093] In one version of the methods described in this patent application 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 Ik"r and
Ito. In one method described in this patent application 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.
[0094] In one version of the methods described in this patent application an
ion channel
' modulating compound is administered to treat andlor prevent rhythm
disturbances by
inhibiting sodium currents of excitation, inhibiting inward Na current
associated with the
plateau of the cardiac action potential (i.e. late window current) and
prolonging refractoriness
mediated by Ik"r and ho. In one method described in this patent application an
ion channel
modulating compound is administered to treat andlor prevent and/or diagnose
rhythm
disturbances by affecting abnormal conduction and prolonging the voltage time
course of
repolarization.
[0095] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to treat andlor 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.
[0096] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to treat and/or prevent the early return
of atrial
fibrillation following electrical cardioversion. In one method described in
this patent
application 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.
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[0097] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to improve atrial contractility andlor to
treat and/or
prevent blood stasis via electrical stunning following a cardiac procedure.
Examples of
cardiac procedures include but are not limited to the maze procedure , surgery
ox 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.
(009] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to diagnose, treat andlor prevent
electrical
abnormalities of the heart in patients suffering from impaired electrical
conduction of the
heart.
(0099] In one version of the methods described in this patent application an
ion channel
modulating compound is administered to diagnose, treat and/or prevent
contractile
dysfunction and/or stunning of the atria. In 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: ~In
one version of the methods described in this patent application an ion channel
modulating
compound is administered to treat andlor prevent vasoconstriction in patients
with reduced
blood flow based upon inhibition of Ito and Ik~.. In one version of the
methods described in
this patent application an ion channel modulating compound is administered to
treat and/or
prevent vasoconstriction by improving blood flood to selected organs and
tissues.
(00101] In one version of the methods described in this patent application an
ion
channel modulating compound Iis administered to treat and/or prevent
vasospasm. In one
version of the methods described in this patent application an ion chaimel
modulating
compound is administered to improve respiratory function based upon relaxation
of smooth
muscle mediated by blockade of Ito and Ik"r resulting in improvements in
airway flow.
(00102] In one version of the methods described' in this patent application an
ion
chamiel modulating compound is administered to treat and/or prevent smooth
muscle spasm.
In one version of the methods described in this patent application an ion
channel modulating
CA 02524034 2005-11-O1
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compound is administered to improve renal function and urinary flow based upon
relaxation
of smooth muscle mediated by blockade of Ito and Ik"r resulting in
improvements in urine
flow. In one version of the methods described in this patent application 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 Ito and Ikur.
[00103] In one version of the methods described in this patent application an
ion
channel modulating compound is administered to treat andlor prevent diseases
ox conditions
which are mediated by inhibiting sodium currents and potassium .currents. In
one version of
the methods described in this patent application an ion channel modulating
compound is
administered to treat andlor prevent diseases or conditions which are mediated
by inhibiting
sodium currents and potassium currents by inhibiting sodium channels and Ik"r
andlor Ito. In
one version of the methods described in this patent application an ion channel
modulating
compound is administered to improve smooth muscle contractile function in body
structures
associated with physiological processes. Example of such 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.
[00104] In one version of the methods described in this patent application an
ion
channel modulating compound is administered to treat and/or prevent diseases
or conditions
of the blood. In one version of the methods described in this patent
application an ion
channel modulating compound is administered to treat and/or prevent diseases
or conditions
of the blood by modifying Ik~. ox Ito. Examples of 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 Ikur or
Ito).
[00105] In one version of the methods described in this patent application an
ion
channel modulating compound is administered to treat andlor prevent diseases
or conditions
of low flow ischemia, shock andlor reperfusion injury. In one version of the
methods
described in this patent application 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 Ik"r
and Ito.
26
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[00106] In one version of the methods described in this patent application an
ion
channel modulating compound is provided as an enzyme modulator. Enzyme that
may be
modulated (inhibited or activated) may include but are not limited to lactate
dehydrogenase
(LDH); kinases such as map lcinases arid other kinases; transaminase; ATPase;
xanthine
oxidase; and Cytochrome oxidase.
[00107] In one version of the methods described in this patent application an
ion
channel modulating compound is provided as an anti-helminthic or vermifuge,
i.e. de-
worming medication for human or other mammals.
[00108] 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 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 xesearch 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 Ito and Ikur and INa. 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 based on its association with the protein
or molecules
mediating Ito and Ik"r and INa. In one version of the methods described in
this patent
application an ion channel modulating compound is used as a ligand or affinity
probe for
proteins or molecules (i.e. ion channels). 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 create antibodies.
]00110] 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 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
27
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used as a research tool or diagnostic tool to identify mechanisms associated
with disease of
the body (such as cardiac disorders).
ION CHANNEL MODULATING COMPOUNDS
[00111] In this section are described various compounds and classes of
compounds that
may be used as ion channel modulating compounds in the methods, formulations,
etc.
described in this patent.
[00112] In this section are first described a series of specific classes of
ion channel
modulating compounds together with specific example compounds, followed by a
general
description of compounds that may be used as ion channel modulating compounds.
Specific Classes oflon Chanzzel Modulating- Compounds and Exemplar Ion
Clzannel
Modulating Compounds
[00113] Examples of specific classes of ion channel modulating compounds and
exemplary ion channel modulating compounds are described below and in U.S.
provisional
patent application number 60/516,248, U.S. patent application number
10/674,684, and U.S.
patent application number 09!913,373, each of which applications is
incorporated herein by
reference in its entirety.
[00114] In the variations described in this section on Spec~c Classes oflon
Channel
Modulatifzg Compounds and Exemplary Ion Claannel Modulating Compouzzds, 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 racernates, 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.
Where a
given structural formula or chemical name is presented for a compound it is
intended that all
possible solvates, pharmaceutically acceptable salts, esters, amides,
complexes, chelates,
stereoisomers, geometric isomers, crystalline or amorphous forms, metabolites,
metablic
precursors or prodrugs of the compound are also separately described by the
chemical '
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structural formula or chemical name.
[00115] As used in this patent, unless the context make plain otherwise, the
following
terms are defined to have following meanings:
"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, malefic acid, malonic acid, succinic acid,
fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
(00116] "Acyl" refers to branched or unbranched hydrocarbon fragments
terminated by
a carbonyl -(C=O)- group containing the specified number of carbon atoms.
Examples
include acetyl [CH3C=O-, a C2acyl] and propionyl [CH3CH2C=O-, a C3acy1].
[00117] "Alkanoyloxy" xefers to an ester substituent wherein the ether oxygen
is the
point of attachment to the molecule. Examples include propanoyloxy [(CH3CH2C=O-
O-, a
C3alkanoyloxy] and ethanoyloxy [CH3C=O-O-, a C~alkanoyloxy).
(00118] "Alkoxy" refers to an O-atom substituted by an alkyl group, for
example,
methoxy [-OCH3, a C I alkoxy] .
[00119] "Alkoxyalkyl" refers to a alkylene group substituted with an alkoxy
group.
For example, methoxyethyl [CH30CH2CH2-] and ethoxymethyl (CH3CHZOCH2-] are
both
C3alkoxyalkyl groups.
[00120] "Alkoxycarbonyl" refers to an ester substituent wherein the caxbonyl
carbon is
the point of attachment to the molecule. Examples include ethoxycarbonyl
[CH3CHZOC=O-,
a C3alkoxycarbonyl] and methoxycarbonyl [GH30C=O-, a CZalkoxycarbonyl].
(00121] "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 C3alkyl), iso-propyl (also a C3alkyl), and t-butyl (a C4alkyl).
[00122] "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 [-CHZCHZCHz-, a C3alkylene~.
[00123] "Alkylcarboxy" refers to a branched or unbranched hydrocarbon fragment
29
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terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl
[HOOC-GHZ-, a CZalkylcarboxy] and carboxyethyl [HOOC-CH2CH2-, a
C3alkylcarboxy].
[00124] "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.
[00125] "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
[C6HSCH2-, a
C~aralkyl group].
[00126] "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 (CSH~-), which is a five carbon
(CS) unsaturated
cycloalkyl group.
[00127] "Carbocyclic" refers to a ring which may be either an aryl ring or a
cycloalkyl
ring, both as defined above.
[00128] "Carbocyclic aryl" refers to aromatic groups wherein the atoms which
form the
aromatic ring are carbon atoms. Cart~ocyclic 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.
[00129] "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.
(00130] "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
"Handbook of Chemistry and Physics," 49th edition, 1965, R.C. Weast, editor;
The Chemical
Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming
Organic
Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include
furanyl,
thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
(00131] "Hydroxyalkyl" refers to a branched or unbranched hydrocarbon fragment
bearing an hydroxy (-OH) group. Examples include hydroxymethyl (-CHzOH, a
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Clhydroxyalkyl) and 1-hydroxyethyl (-CHOHCH3, a C2hydroxyalkyl).
[00132] "Thioalkyl" refers to a sulfur atom substituted by an alkyl group, for
example
thiomethyl (CH3S-, a C~thioalkyl).
[00133] "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. Thus, 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.
[00134] "Pharmaceutically acceptable carriers" for therapeutic use are well
known in
the pharmaceutical art, and are described, for example, in Remin~tons
Pharmaceutical
Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, 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.
For example,
sodium benzoate, sorbic acid and esters ofp-hydroxybenzoic acid may be added
as
preservatives. Id. at 1449. In addition, antioxidants and suspending agents
may be used. Id.
[00135] "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.
Aminocyclah~xxyl Ether Iort Channel lVfodulating 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:
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~ 1=
5~ ~3
4
(A)
[00137] The bonds front 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 traps
relationship. In
one variation, the stereochemistry of the amine and ether substituents of the
cyclohexane ring
is either (R,R)-tr~ahs or (S,S)-traps. In another variation, the
stereochemistry at these
positions is either (R,S)-cis or (S,R)-cis.
[00138] In one version of the amino cyclohexyl ether ion channel modulating
compounds, the ion channel modulating compound is a compound of the formula:
R5
A~
1
N
R R2
4
R3
[00139] Compounds of formula (J7 are aminocyclohexyl ethers. More
specifically,
these aminocyclohexyl ethers axe substituted at position 2 of the cyclohexyl
ring with an
amine group -NRIR2. The cyclohexyl ring rnay also be substituted with
additional
substituents (designated as R3 and R4) as described in more detail below.
Examples of
specific compounds represented by formula ()] are described below.
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[00140] Depending upon the selection of substituents Rl and Rz, the compounds
of
formula (I) may be primary, secondary, or tertiary amines (i.e., both Rl and
Rz are hydrogen,
only one of RI and Rz is hydrogen, or neither of Rl and Rz are hydrogen,
respectively). In one
embodiment of the invention, the compounds of formula (I) are tertiary amines,
i.e., neither
RI nor Rz is hydrogen. Where the amine is tertiary, it may be a cyclic amine.
Amine
substituents Rl and Rz may be independently selected from substituents which
include
hydrogen, alkyl groups containing from one to eight carbon atoms (i.e., CI-
C$alkyl),
alkoxyalkyl groups containing from three to eight carbon atoms (i.e., C3-
C$alkoxyalkyl), alkyl
groups containing from one to eight carbon atoms where one of the carbon atoms
is
substituted with a hydroxyl group (i.e., C~-Cshydroxyalkyl), and aralkyl
groups containing
from seven to twelve carbon atoms (i.e., C~-Clzaralkyl). In one version, RI
and R2 are
independently selected from hydrogen, C1-CBalkyl, C3-CBalkoxyalkyl, C1-
CBhydroxyalkyl,
and C~-Clzaralkyl. In another version, Rl and Rz are independently selected
from
C3-CBalkoxyalkyl, C1-C$hydroxyalkyl, and C~-Clzaralkyl.
[00141] Alternatively, Rl and Rz, when taken together with the nitrogen atom
to which
they are directly attached in formula (I), may form a ring denoted by formula
(IIJ:
~N RI
Ra
wherein the ring of formula (II) 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 sub'stituents selected from hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, Cz-
C4acyl,
C1-C3alkyl, Cz-C4alkylcarboxy, C1-C3alkoxy, C~-Czoalkanoyloxy, or may be
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 C3-CBCarbocyclic
ring, and any
one or more of the additional nitrogen ring atoms may be substituted with
substituents
selected from hydrogen, CI-C~alkyl, Cz-C4acyl, Cz-C~hydroxyalkyl and C3-
C$alkoxyalkyl.
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Examples of substituents containing a fused ring system include the
pexhydroindolyl and
1,2,3,4-tetrahydroisoquinolinyl groups.
[00142] In connection with the ring of formula (In, any two adjacent ring
atoms may
be joined together by single or double bonds. Thus, the ring of formula (I~
may be saturated
or unsaturated, and an unsaturated ring may contain one, or more than one,
sites of
unsaturation. In other words, 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.
[00143] Alternatively, Rr and R2, when taken together with the 2-amino
nitrogen of
formula (n, may complete a bicyclic ring. Bicyclic rings include, for example,
3-azabicyclo[3.2.2~nonane, 2-azabicyclo[2.2.2]octane,3-
azabicyclo[3.1.0]hexane, and
3-azabicyclo[3.2.0]heptane. For these derivatives, the 2-substituents of the
cyclohexyl ethers
of formula (~ are the following groups: 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.
[00144] R1 and R2, when taken together may contain only a single heteroatom.
Preferred heteroatoms include nitrogen, oxygen and sulfur. An example of a
ring in which Rl
and R2 together include an oxygen heteroatom is the morpholinyl group. An
example of a
ring where Rl and RZ together include a second nitrogen heteroatom is the
piperazinyl group.
[00145] Cyclohexane substituents R3 and R4 may be independently attached to
ring
positions 3, 4, 5 or 6 (i.e., both R3 and R4 may be attached to the same ring
position or each
attached to different ring positions). R3 and Rø are independently selected
from hydrogen,
hydroxy, C1-C6alkyl, and CI-C6alkoxy, ands when both R3 and Rø 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.
[0100] Depending upon the identity of X, the ether side chain, -CH(RS)-X-A, in
formula (I)
may take several forms. For example, a compound of formula (I) may have X as a
-C(Rb,Rl4)-Y- group, where Y may be any of a direct bond, an oxygen atom (O),
a sulfur
atom (S) or a C1-C~alkylene group. R6 and R~4 are independently selected from
hydrogen,
CI-C6alkyl, aryl and benzyl, or R~ and RI4, when taken together With the
carbon to which they
are attached, may form a spiro C3-Cscycloalkyl. Thus, compounds of the
invention include
compounds of formula (I) where R.6 and R14 are hydrogen and Y is a direct
bond, such that X
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may be CH2.
[0101] Alternatively, X may be an alkenylene moiety, e.g., a cis-or trafis-
alkenylene moiety,
C(RI3)=CH, where R~3 may be any of hydrogen, C1-C6alkyl, C3-CBCycloalkyl, aryl
or benzyl.
For compounds of formula (I) where X is an alkenylene moiety, X is preferably
a
traps-alkenylene moiety.
[0102] Alternatively, X may be a direct bond. Independent of the selections
for A, X and
other variables, RS is selected from hydrogen, C1-C6alkyl, aryl and benzyl.
[0103] In one variation, X is either a -C(R4,RI4)-Y- or a C(R13)=CH group, and
is not a direct
bond. In another variation, the compounds of the invention exclude those
compounds
wherein X is a direct bond when Rl and RZ are hydrogen. In another variation,
X is selected
from a direct bond, -C(Rb,R~4)-Y-, and -C(R13)=CH-, with the proviso that when
X is a direct
bond and A is formula (IIIJ then at least one of R~, R$ and R9 is not
hydrogen. In another
variation, the compounds of the invention exclude those compounds wherein X is
a direct
bond when A is formula (III) and each of R~, R$ and R9 is hydrogen. In another
variation, the
compounds of the invention exclude those compounds wherein X is a direct bond
when A is
formula (DI).
[0104] Ether side chain component A is generally a hydrophobic moiety.
Typically, 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 C5-Cl2alkyl and C3-
Cl3carbocyclic
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 (III), (IV), (V), (VIJ, (VIn, or (VIII) respectively.
[0105] A suitable "A" group in the formula above is a phenyl ring represented
by formula
(~:
R7
'/
R$
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
where R~, R$ and R9 are independently selected from bromine, chlorine,
fluorine, carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl,
C2-C~alkanoyloxy, CI-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-
C6thioalkyl, aryl and
N(RIS,Ri6) where R15 and Rlb axe independently selected from hydrogen, acetyl,
methanesulfonyl, and C1-C6alkyl.
[0106] Fox compounds of formula (I) where X is a direct bond or CH2, at least
one of R~, R8
and Rg is preferably selected from amine (-NR~sRIS, where RIS and RI6 are
independently
hydrogen, acetyl, methanesulfonyl, and C1-C6alkyl), bromine, chlorine,
fluorine, carboxy,
hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl, C~-C~alkanoyloxy, C~-
C6alkyl,
CI-C6alkoxy, Cz-C~alkylcarbonyl, Cl-C6thioalkyl or aryl groups. Fox compounds
of formula
(n when X is CH=CH, and R3 and R4 are hydrogen, at least one of R~, R8 and R9
is preferably
a substituent other than hydrogen. In one variation, the present invention
provides
compounds of formula (I) where A includes phenyl groups of formula ()~ such
that at least
one of R~, R8 and R9 is not hydrogen, i. e., formula (III) is a phenyl group
that contains at least
one non-hydrogen substituent. In another variation, R~, R$ and R9 are selected
from amine
(-NR1sR16, where R15 and R16 are independently hydrogen, acetyl,
methanesulfonyl, and
C~-C6alkyl), bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxyrnethyl, nitro,
trifluoromethyl, CZ-C~alkanoyloxy, CI-C6alkyl, C1-C6alkoxy, CZ-
C~alkylcarbonyl~and
C1-C6thioalkyl, i.e., none of R~, R8 or R9 is aryl. In another variation, A
does not include a
phenyl ring of formula (IIl] when X is a direct bond.
[0107] Other suitable "A" groups are 1-naphthyl groups as represented by
formula (I~:
/ \
R1o R1 i
\ /
(~)
where Rlo and Rl1 are independently selected from bromine, chlorine, fluorine,
carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl,
C2-C7alkanoyloxy, C~-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, CI-
C6thioalkyl, and
36
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N(Ris,R~s) where Rls and RI6 are independently selected from hydrogen, acetyl,
methanesulfonyl, arid C1-C6alkyl.
[0108] Other suitable "A" groups are 2-naphthyl group as represented by
formula (V):
/ \
R1 o R1 t
\ /
(V)
where Rlo and RI I are independently selected from bromine, chlorine,
fluorine, carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl,
Ca-C~alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, CZ-C7alkoxycarbonyl, CI-
C6thioalkyl, and
N(Rls,Ris) where RIS and R16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and CI-C6alkyl, as defined above.
j0109] Other suitable "A" groups are aromatic groups represented by formula
(VI):
/
:. , Rl2 \ Z
where RIZ is selected from bromine, chlorine, fluorine, carboxy, hydrogen,
hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, CZ-
C~alkanoyloxy,
C~-C6alkyl, C~-C6alkoxy, CZ-C~alkoxycarbonyl, CI-C6thioalkyl, and N(RIS,Ri6)
where Rls
and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and
CI-C6alkyl;
and Z is selected from CH, CH2, 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 R17
when Z is N,
and Rl~ is selected from hydrogen, CI-Cbalkyl, C3-Cscycloalkyl, aryl and
benzyl.
[0110] The aryl groups of formula (VZ) 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
37
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N-R17, and in a particularly preferred embodiment Z is O or S.
[0111] Another suitable "A" group is acenaphthyl groups as represented by
formula (VII):
/ \
\ /
(VII)
(0112] Still another suitable "A" group is the fluorenyl group represented by
formula (VIII):
w
/ \ /
[0113] In some variations, ether side chain component A is an acenapthyl or
fluorenyl group
only when X is a direct bond or CHZ. In other variations, the acenaphthyl
group is a
1-acenaphthyl group, and the fluorenyl group is a 9-fluorenyl group.
(0114] In a particular variation of formula (n, X is (CHZ)-Y. For these
variations, Y is
preferably a direct bond, an oxygen atom, or a sulfur atom. In a another
variation, Y is a
direct bond or an oxygen atom. In still another variation Y is a direct bond
and X is
C(R6,Ri4), where R6 and RI4 are as defined above. In yet another variation, X
is C(RI3)=CH,
and R13 is a hydrogen atom. For these variations, R3 and R~ may be
independently attached to
the cyclohexane ring at the 4- ox 5- positions.
[0115] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (I),
wherein: independently at each occurrence,
X is selected from a direct bond, -C(R6,R14)-Y- and -C(R.13)=CH--, with the
proviso that when X is a direct bond and A is formula (III) then at least one
of R~, R8 and R9
is not hydrogen;
38
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Y is selected from a direct bond, O, S and C~-C4alkylene;
RI3 is selected from hydrogen, C~-C6alkyl, C3-CBCycloalkyl, aryl and benzyl;
RI and RZ are independently selected from hydrogen, C1-C$alkyl,
C3-C$alkoxyalkyl, C1-C$hydroxyalkyl, and C~-ClZaralkyl; or
R~ and RZ are independently selected from C3-C$alkoxyalkyl, Ci-
C$hydroxyalkyl, and C~-Cl2aralkyl; or
Rl and R2, when taken together with the nitrogen atom to which they are
directly attached in formula (17, foam a ring denoted by formula (I)]:
~N R
Ra
wherein the ring of formula (II) 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
bond's, and
where any one or more of the additional carbon ring atoms may be substituted
with one or
two substituents selected from hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, CZ-
C4acyl,
C1-C3alkyl, CZ-C4alkylcarboxy, CI-C3alkoxy, C~-CZoalkanoyloxy, or may be
substituted to
form a spiro eve- 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 C3-Cscarbocyclic ring, and any one or more of the additional
nitrogen ring atoms
may be substituted with substituents selected from hydrogen, C1-C6alkyl, C2-
C4acyl,
C2-C4hydroxyalkyl and C3-Cgalkoxyalkyl; or
Rl and R2, when taken together with the nitrogen atom to which they are
directly attached in formula (1], 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;
R3 and R4 are independently attached to the cyclohexane ring shown in
formula (n at the 3-, 4-, 5- or 6- positions and are independently selected
from hydrogen,
hydroxy, C~-C6alkyl and C1-C6alkoxy, and, when both R3 and R4 are attached to
the same
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cyclohexane ring atom, may together form a spiro five- or six-membered
heterocyclic ring
containing one or two heteroatoms selected from oxygen and sulfur;
R5, R6 and RI4 are independently selected from hydrogen, CI-C6alkyl, aryl and
benzyl, or R6 and RI4, when taken together with the carbon to which they are
attached, may
form a spiro C3-CSCycloalkyl;
A is selected from CS-CIZalkyl, a C3-Cl3carbocyclic ring, and ring systems
selected from foxmulae (Ill], (IV), (V), (VI), (VII) and (VITI):
R7 \
R
s
where R~, R$ and R9 are independently selected from bromine, chlorine,
fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl,
trifluoromethyl, C2-C~alkanoyloxy, CI-C6alkyl, CI-C6alkoxy, CZ-
C7alkoxycarbonyl,
C1-C6thioalkyl and N(Ri~,Rl6) where Rls and R16 are independently selected
from hydrogen,
acetyl, methanesulfonyl and CI-C6alkyl;
/ \ / \
Rlo \ / Rn Rio Rn
and ~ /
where RIO and RI I are independently selected from bromine, chlorine,
fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,
sulfamyl,
trifluoromethyl, CZ-C~alkanoyloxy, C1-C6alkyl, CI-C6alkoxy, CZ-
C~alkoxycarbonyl,
C1-Cbthioalkyl, and N(R15,RI6) where RIS and Rlb are independently selected
from hydrogen,
acetyl, methanesulfonyl, and CI-C6alkyl;
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Ria \ Z/
where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen,
hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl,
CZ-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C~alkoxycarbonyl, CI-
C6thioalkyl, and
N(Rls,Ri6) where Rls and R16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C1-C6alkyl; and Z is selected from CH, CH2, O, N and S,
where Z may
be directly bonded to "X" as shown in formula (l~ when Z is CH or N, or Z rnay
be directly
bonded to RI~ when Z is N, and R17 is selected from hydrogen, C~-C6alkyl, C3-
CBCycloalkyl,
aryl and benzyl;
/ \
\ ~ / ~ ~ \
(Va? C~
including isolated enantiomeric, diastereomeric and geometric isomers thereof
and solvates and/or pharmaceutically acceptable salts of any of the foregoing.
(0116] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (IX), or a
solvate or
pharmaceutically acceptable salt thereof:
~X~O R~
N
\R2
R3
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wherein, independently at each occurrence,
X is selected from a direct bond, -CH=CH- and -C(R6,Rla,)-Y-;
Y is selected from a direct bond, O and S; and
Rl, R2, R3, R4, Rg, R7, R$, R9, Rlo, Rl ~, R12, R14, A and Z are defined as
above
for compounds of formula (I).
[0117] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (X), or a
solvate or
pharmaceutically acceptable salt thereof:
A~ ~
X~O R~
N
\ R2
R3
wherein, independently at each occurrence,
X is selected from a direct bond, -CH=CH- and -C(R6,R14)-Y-;
Y is selected from a direct bond, O, and S;
Rl, R2, Rs and R14 are defined as above for.compounds of formula (l~;
R3 and R4 are independently attached to the cyclohexane ring at the 4- or
5-positions, and are independently selected from hydrogen and Cl-C6alkoxy; and
A is selected from CS-Cl2alkyl, C3-C$cycloalkyl, and any of formulae (III),
(IV), (V), and (VI) as above for compounds ~of formula (I), wherein Z, R~, R8,
R9, Rlo, Ri i and
RIZ are defined as above for compounds of formula (I).
[0118] In another version of the amino eyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XI), or a
solvate or
pharmaceutically acceptable salt thereof:
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O
A~ O R~
N
\ R2
R3
wherein, independently at each occurrence,
Rl and R2 are defined as above for compounds of formula (I);
R3 and R4 are independently attached to the cyclohexane ring at the 4- or
5-positions, and are independently selected from hydrogen and methoxy; and
A is selected from CS-Clzalkyl, C3-C$cycloalkyl, and any of formulae (I~,
(I~, (~, and (VIJ as above for compounds of formula (IJ, wherein Z, R~, R8,
R9, Rlo, Rl1 and
RIZ are defined as above for compounds of formula (IJ.
[0119) In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XII), or. a
solvate or
pharmaceutically acceptable salt thereof:
A
O R1
,N,~
R2
wherein, independently at each occurrence,
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RI and R2 are defined as above for compounds of formula (I);
R3 and R4 are independently attached to the cyclohexane ring at the 4- or
5-positions, and are independently selected from hydrogen and methoxy; and
A is selected from CS-Cl2alkyl, C3-C$cycloallcyl, and any of formulae (ITI),
(IV), (~, and (VI) as above for compounds of formula (I), wherein Z, R7, R8,
R9, Rlo, RI1 and
R~2 are defined as above for compounds of formula (I).
[0120] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XII)], or a
solvate or
pharmaceutically acceptable salt thereof:
A.~ ~
~Q R~
N~
R2
Rs
wherein, independently at each occurrence,
X is selected from -C(R6,R14)-Y- and -CH=CH-;
Y, R~, RZ, R6 and RI4 axe defined as above for compounds of formula (17;
R3 and R4 are independently attached to the cyclohexane ring at the 4- or
5-positions, and are independently selected from hydrogen and methoxy; and
A is selected from C3-C$cycloalkyl and any of formulae (111J, (I~, (V), (VI),
(VIA and (V)II) as above fox compounds of formula (I), where Rs and R9 are
defined as above
for compounds of formula (IJ; R~, Rio, R~ 1 and RIZ are hydrogen, and Z is
selected from O, S
and N-Rl~ where Rl~ is selected from hydrogen and methyl.
[0121] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XI~, or a
solvate or
pharmaceutically acceptable salt thereof:
44
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O
A/ O R~
N.~
R2
(
wherein, independently at each occurrence,
Rl and Ra are defined as above for compounds of formula (I);
A is selected from any of formulae (III), (IV), (V) and (V)] as above for
compounds of formula (I), wherein R7, Rin, Rl I, and R12, are hydrogen, R$ and
R9 are
independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine,
methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl,
thiomethyl,
trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NHZ, with the proviso that
at least one of
R$ and.R9 is not hydrogen; and Z is selected from O and S.
[0122] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the'formula (XV), or a
solvate or
pharmaceutically acceptable salt thereof:
A
11
N.~
R2
(XV)
wherein, independently at each occurrence,
RI and R~ are defined as above for compounds of formula (1); and
A is selected from any of formulae (II)], (IV), (V) and (VI) as defined above
CA 02524034 2005-11-O1
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for compounds of formula (I), wherein R~, Roc, R> >, and Rlz, are hydrogen, R$
and R9 are
independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine,
methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl,
thiomethyl,
trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH2, With the proviso that
at least one of
R$ and R9 is not hydrogen; and Z is selected from O and S.
[01231 In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XVI), or a
solvate or
pharmaceutically acceptable salt thereof:
A~X~O R~
R2
(~~
wherein, independently at each occurrence,
X is selected from a direct bond, traps-CH=CH-, -CHZ- and -CHZ-O-;
Rl and RZ are both methoxyethyl or, when taken together with the nitrogen
atom to which they are attached, complete a ring selected from pyrrolidinyl, 2-
ketopyrrolidinyl, 3-ketopyrrolidinyl, 2-acetoxypyrrolidinyl, 3-
acetoxypyrrolidinyl, 2-
hydroxypyrrolidinyl, 3-hydroxypyrrolidinyl, thiazolidinyl, piperidinyl, 2-
ketopiperidinyl, 3-
ketopiperidinyl, 4-ketopiperidinyl, acetylpiperazinyl, 1,4-dioxa-7-
azaspiro[4.4]non-7-yl,
hexahydroazepinyl, morpholinyl, N-methylpiperazinyl and 3-
azabicyclo[3.2.2]nonanyl; and
A is selected from cyclohexyl, rnonochlorophenyl, 2,6-dichlorophenyl,
3,4-dichlorophenyl, 2 bromophenyl, 2,4-dibromophenyl, 3-bromophenyl, 4-
bromophenyl,
3,4-dimethoxyphenyl, 1-naphthyl, 2-naphthyl, 3-benzo(b)thiophenyl, 4-
benzo(b)thiophenyl,
(2-trifluoxornethyl)phenyl, 2,4-di(trifluoromethyl)phenyl, and (4-
trifluoromethyl)phenyl.
[0124) In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the fornmla (XVII), or a
solvate or
pharmaceutically acceptable salt thereof:
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R19
O-~CH n
Rl8 Rao
N O
(X'~
wherein, independently at each occurrence,
n is selected from 1, 2 and 3;
Rl8 is either hydrogen or methyl and is independently attached to the
cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-
positions;
RI9 is selected from a group consisting of bromine, chlorine, fluorine and
hydrogen; and .
RZO is selected from a group consisting of bromine, chlorine and fluorine;
including isolated enantiomeric, diastereomeric and geometric isomers thereof.
In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound that is a traps
configuration of formula
(XVII) as represented by formula (XVIII), or a solvate or pharmaceutically
acceptable salt
thereof:
Ri 9
O-ECH n
Rl8 Rao
N O
wherein, independently at each occurrence,
n is selected from 1, 2 and 3;
R~8 is either hydrogen or methyl and is independently attached to the
cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-
positions;
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R~9 is selected from a group consisting of bromine, chlorine, fluorine and
hydrogen; and
RZO is selected from a group consisting of bromine, chlorine and fluorine;
including isolated enantiomeric, diastereomeric and geometric isomers thereof.
[0125) In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (IX~; or a
solvate or
pharmaceutically acceptable salt thereof
R19
.O~CH n ~ ~ ~
Rl8 Rao
~N
O
(
wherein, independently at each occurrence,
n is selected from l, 2 and 3;
Rl$ is either hydrogen or methyl and is independently attached to the
cyclohexane ring shown in formula (XVII) at one of the 3-, 4-, 5- or 6-
positions;
R19 is selected from a group consisting of bromine, chlorine, fluorine and
hydrogen; and
RZO is selected from a group consisting of bromine, chlorine and fluorine;
including isolated enantiomeric, diastereomeric and geometric isomers thereof.
[0126) In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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 amorphous form, metabolite,
metabolic precursor or
prodrug thereof:
48
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Rs
R4
/J
R
s
f~/~'OH
(~)
wherein, R3, R4 and RS are independently selected from hydrogen, hydroxy and
C~-Cgalkoxy, including isolated enantiomeric, diastereomeric and geometric
isomers thereof,
and mixtures thereof, with the proviso that R3, R4 and RS cannot all be
hydrogen.
[0127] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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.
(0128] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XX), or a solvate,
pharmaceutically acceptable salt thereof, wherein, R4 and RS are independently
selected from
hydroxy and C1-Cbalkoxy, including isolated enantiomeric, diastereomeric and
geometric
isomers thereof, and mixtures thereof.
[0129] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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, R3 is hydrogen, R4
and R5 axe
independently selected from hydroxy and CI-C6alkoxy.
[0130] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ian 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 amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, R4 and RS are
independently selected
from Ci-C6alkoxy.
[0131] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
49
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the ion chaimel modulating compound is compound of formula (XX), or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastexeomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
independently selected from C1-C6alkoxy.
[0132] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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 amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, 8315 hydrogen, R4 and RS are Clalkoxy.
[0133] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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, R3 is hydrogen, Rø
and RS are
C 1 alkoxy.
[0134] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
R3
O
Ra
N R
V OH
prodrug thereof:
wherein, R3, R4 and RS are independently selected from hydrogen, hydroxy and
C1-C6alkoxy, including isolated enantiomeric, diastereomeric and geometric
isomers thereof,
and mixtures thereof.
[0135] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion chamiel modulating compound is compound of formula (XXI), or a
solvate,
CA 02524034 2005-11-O1
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pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof.
[0136] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt thereof, wherein, Rø and R5 are independently
selected from
hydroxy and C1-C6alkoxy, including isolated enantiomeric, diastereomeric and
geometric
isomers thereof, and mixtures thereof.
(0137] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (:~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, Rø
and RS are
independently selected from hydroxy and C1-C6alkoxy.
[0138] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXIJ, or a
solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, R4 and RS are
independently selected , ,
from CI-C6alkoxy.
[0139] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (:~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS axe
independently selected from C 1-C6alkoxy.
[0140] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, R4 and RS are
Clalkoxy.
[0141] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
51
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the ion channel modulating compound is compound of formula (XXI), or a
solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomexic and
geometric isomers thereof, arid mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
C I alkoxy.
[0142] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXII), or a
solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof:
R3
.O
Rd
N R/ J
~~'OH
wherein, R3, R4 and RS are independently selected from hydrogen, hydroxy and
~CI-C6alkoxy, including isolated enantiomeric, diastereomeric and geometric
isomers thereof,
and mixtures thereof.
[0143] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof.
[0144] In another version of the aminocyclohexyl ethex ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXII), or a
solvate,
pharmaceutically acceptable salt thereof, wherein, R4 and RS are independently
selected from
hydroxy and C1-C6alkoxy, including isolated enantiomeric, diastereomeric and
geometric
isomers thereof, and mixtures thereof.
[0145] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
52
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independently selected from hydroxy and CI-C6alkoxy.
[0146] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXII), or a
solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, RQ and RS are
independently selected
from C~-C6alkoxy.
[0147] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
independently selected from C1-C6alkoxy.
[0148] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, R4 and RS are
Clalkoxy.
[0149] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXII), or a
solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
C I alkoxy.
[0150] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXIIn, or a
solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
Rs
,0
Ra
\N
I ~ Rs
53
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prodrug thereof:
wherein, R3, R~ and RS are independently selected from hydrogen, hydroxy and
CI-Cbalkoxy, including isolated enantiomeric, diastereomeric and geometric
isomers thereof,
and mixtures thereof.
[0151] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel :modulating compound is compound of formula (~:XIII), or a
solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof.
[0152] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXI11), or a
solvate,
pharmaceutically acceptable alt thereof, wherein, R4 and RS are independently
selected from
hydroxy and CI-C6alkoxy, including isolated enantiomeric, diastereomeric and
geometric
isomers thereof, and mixtures thereof.
[0153] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
independently selected from hydroxy and Cl-C6alkoxy.
[0154] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (, or a solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, R4 and RS are
independently selected
from C1-C6alkoxy.
[0155] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion chamiel modulating compound is compound of formula , or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
independently selected from C1-C6alkoxy.
54
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[0156] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXIII), or a
solvate,
pharmaceutically acceptable salt, ester, amide, complex, chelate,
stereoisomer, stereoisomeric
mixture, geometric isomer, crystalline or amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R3 is hydrogen, R4 and RS are
Clalkoxy.
[0157] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (~, or a solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R3 is hydrogen, R4
and RS are
Clalkoxy.
[0158] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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 amorphous form, metabolite,
metabolic precursor or
.O \ RQ
\,~
\ Rs
prodrug thereof:
Cue)
wherein, Rø and RS are independently selected from hydrogen, hydroxy and
CI-C6alkoxy, including isolated enantiomeric, diastereomeric and geometric
isomers thereof,
and mixtures thereof:
[0159] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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.
[0160] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (XXIV), or a
solvate,
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pharmaceutically acceptable salt thereof, wherein, R4 and R5 are independently
selected from
hydroxy and CI-C6alkoXy, including isolated enantiomeric, diastereomeric and
geometric
isomers thereof, and mixtures thereof.
[0161] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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, R4 and RS are
independently
selected from hydroxy and CI-C3alkoxy.
[0162] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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 amorphous form, metabolite,
metabolic precursor or
prodrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R4 and RS are independently selected
from
C1-C6alkoxy.
[0163] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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, R4 and RS are
independently
selected from CI-C3alkoxy.
[0164] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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 axriorphous form, metabolite,
metabolic precursor or
pradrug thereof, including isolated enantiomeric, diastereomeric and geometric
isomers
thereof, and mixtures thereof, wherein, R4 and RS are Clalkoxy.
[0165] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is compound of formula (X~IV), or a
solvate,
pharmaceutically acceptable salt thereof, including isolated enantiomeric,
diastereomeric and
geometric isomers thereof, and mixtures thereof, wherein, R4 and RS are
Clalkoxy.
[0166] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
56
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the ion channel modulating compound is a compound of the formula (XXV),
R3
O
-Ra
N
Rs
V -OH
wherein:
R3, R4 and RS are independently selected from hydrogen, hydroxy and
C1-C6alkoxy; or,
R3, R4 are independently selected from hydroxyl and C1-C6alkaxy and RS is
hydrogen; or,
R3, R4 are both CI-C6alkoxy and RS is hydrogen; or
R3, R~ are both methoxy and RS is hydrogen; or
including isolated eriantiomeric, diastereomeric and geometric isomers
thereof, and mixtures thereof, with the proviso that R3, R4 and RS cannot all
be hydrogen; and
~~~~ indicates a bond that provides a R stereoisomer or a S stereoisomer at
the position to which the bond is attached.
[0167] In one variation, the hydroxyl substituent is positioned at the 3
position of the
pyrrolidinyl ring in (XXV). In another variation, the stereochemistry at the
position of the
cycloalkyl ring of (~~ containing the nitrogen group is racemic, which may be
provided
for any of the variations mentioned above.
[0168] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (~XVI):
R
.(7 ~ ~~\ 3
,R
1
R4
R2
57
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wherein:
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-1 and C-2 carbons
of the
cyclohexyl group may be either R,R configuration or S,S configuration;
Rl and Rz are independently selected from hydrogen, C~-CBalkyl, C3-
CBalkoxyalkyl, C1-
C$hydroxyalkyl, and C7-Clzaralkyl; or
Rl and Rz are independently selected from C3-CBalkoxyalkyl, CI-C$hydroxyalkyl,
and
C7-C~zaralkyl; or
Ri and R2, are taken together with the nitrogen atom to which they are
dixectly
attached in formula (XXVI) to form a ring denoted by formula (f~:
~-- ~--R~
N
-. R2
wherein the ring of formula (IV) 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~-C3hydroxyalkyl, oxo, Cz-
C~acyl, Cz-
C3alkyl, Cz-C4alkylcarboxy, C1-C3alkoxy, CI-Czoalkanoyloxy, 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
C3-CBCarbocyclic ring, and any one or more of the additional nitrogen ring
atoms may be
substituted with substituents selected from hydrogen, CI-Csalkyl, Cz-Caacyl,
Cz-
C4hydroxyalkyl and C3-Csalkoxyalkyl; or
Rl and R2 are taken together to form
OH
wherein the OH group may be at any position on the pyrrolidinyl ring,
including the 3-
position;
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R~ and Rz, 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;
R3 and R4 are independently selected from bromine, chlorine, fluorine,
carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl,
Cz-C~alkanoyloxy, C~-C6alkyl, CI-C6alkoxy, Cz-C~alkoxycarbonyl, C1-C6thioalkyl
and
N(R15,R~6) where R15 and R16 are independently selected from hydrogen, acetyl,
methanesulfonyl and C1-C6alkyl; and
[0169] In one version of formula (XXVIJ, R3 and R4 are independently selected
from
hydrogen, hydroxyl and CI-C6alkoxy. In another version of formula (XXVI), both
R3 and R~
are C~-C6alkoxy. In another variation, both R3 and R4 are methoxy. In still
another variation
of formula (XXVI), R3 and R4 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.
[0170] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XXVII), or
pharmaceutically acceptable salts or solvates thereof.
O ~ OCH3
3
."~uiIIOH OCH
(XXVIIJ
(1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
[0171) In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound of the formula (XXV>II),
59
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O ~ OCH3
..~,,' 3
///N ."unlOH OCH
.HC1
(xxvl>T>
(1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride.
[0172] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
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:
(1R,2R)-[2-(4-morpholinyl)-1-(2-naphthenethoxy)] ~O /
cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-(2-
N ~ /
naphthenethoxy)) cyclohexane or a mixture of (1R,2R)-
.. [2-(4-morpholinyl)-1-(2-naphthenethoxy)]cyclohexane
O
and (1S,2S)-[2-(4-morpholinyl)-1-(2-
naphthenethoxy)]cyclohexane
/
(1R,2R)-[2-(4-morpholinyl)-1-(1-naphthenethoxy)J
cyclohexane or (1S,2S) -[2-(4-morpholinyl)-1-(1-
naphthenethoxy)J cyclohexane or a mixture of (1R,2R)-
[2-(4-morpholinyl)-1-(1-naphthenethoxy)J cyclohexane
and (1S,2S) -[2-(4-morpholinyl)-1-(1-naphthenethoxy)]
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r,
(1R,2R)-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]
cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-(4- ~Br
bromophenethoxy)] cyclohexane or a mixture of
(1 R,2R)-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]
cyclohexane and (1S,2S)-[2-(4-morpholinyl)-1-(4-
bromophenethoxy)] cyclohexane
( 1 R,2R)-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)
ethoxy]] cyclohexane or (1S,2S) -[2-(4-morpholinyl)-1- ~ ~O ~
[2-(2-naphthoxy)ethoxy]] cyclohexane or a mixture of
( 1 R,2R)-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)
ethoxy]] cyclohexane and (1S,2S) -[2-(4-morpholinyl)-
1-[2-(2-naphthoxy)ethoxy]] cyclohexane
Br
(1R,2R)-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)
ethoxy]] cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1- O
[2-(4-bromophenoxy) ethoxy]] cyclohexane or a
mixture of (1R,2R)-[2-(4-morpholinyl)-1-[2-(4-
bromophenoxy) ethoxy]] cyclohexane and (1S,2S)-[2-
(4-morpholinyl)-1-[2-(4-bromophenoxy) ethoxy]]
cyclohexane
/ OMe
( 1 R,2R)-[2-(4-morpholinyl)-1-(3,4-dimethoxyphen
OMe
ethoxy)] cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-
(3,4-dimethoxyphen ethoxy)] cyclohexane or a mixture
of (1R,2R)-[2-(4-morpholinyl)-1-(3,4-dimethoxyphen
ethoxy)] cyclohexane and (1S,2S)-[2-(4-morpholinyl)-
1-(3,4-dimethoxyphen ethoxy)] cyclohexane
61
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(1R,2R)-[2-(1-pyrrolidinyl)-1-(1-naphthenethoxy)]
cyclohexane ox (1S,2S)-[2-(1-pyrrolidinyl)-1-(1-
naphthenethoxy)] cyclohexane or a mixture of (1R,2R)-
[2-(1-pyrrolidinyl)-1-(1-naphthenethoxy)] cyclohexane
and (1S,2S)-[2-(1-pyrrolidinyl)-1-(1-naphthenethoxy)]
cyclohexane
,O
( 1 R,2R)-[2-(4-morpholinyl)-1-(2-(benzo [b]thiophen-3-
yl)] cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-(2- N S
(benzo[b]thiophen-3-yl)] cyclohexane or a mixture of
( 1 R,2R)-[2-(4-morpholinyl)-1-(2-(benzo [b]thiophen-3- O
yl)] cyclohexane and (1S,2S)-[2-(4-morpholinyl)-1-(2-
(benzo[b]thiophen-3-yl)] cyclohexane
(1R,2R)-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-4-
O S
yl)] cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-(2-
(benzo[b]thiophen-4-yl)]cyclohexane or a mixture of ~ /
1R,2R - 2- 4-mo holin 1 -1- 2 enzo b thin hen-4-
( )[ ( ~ Y) ( -~ [ ] p -
yl)] cyclohexane and (1S,2S)-[2-(4-morphohnyl)-1-(2
O
(benzo[b]thiophen-4-yl)]cyclohexane
~ Br
( 1 R,2R)-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]
cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-(3-
bromophenethoxy)] cyclohexane or a mixture of
(1 R,2R)-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]
cyclohexane and (1S,2S)-[2-(4-morpholinyl)-1-(3-
bromophenethoxy)] cyclohexane
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Br
O
( 1 R,2R)-[2-(4-morpholinyl)-1-(2-bromophenethoxy)]
cyclohexane or (1S,2S)-[2-(4-morpholinyl)-1-(2- N \
bromophenethoxy)] cyclohexane or (1R,2R)-[2-(4-
morphohnyl)-1-(2-bromophenethoxy)] cyclohexane O
and (1S,2S)-[2-(4-morpholinyl)-1-(2-
bromophenethoxy)] cyclohexane
~ OMe
(1R,2R)-[2-(4-motpholinyl)-1-(3-(3,4-
,O
dimethoxyphenyl) propoxy)] cyclohexane or OMe
(1 S,2S)-[2-(4-morpholinyl)-1-(3-(3,4-
dimethoxyphenyl) propoxy)] cyclohexane or a mixture
of (1R,2R)-[2-(4-morpholinyl)-1-(3-(3,4- O
dimethoxyphenyl) propoxy)] cyclohexane and
(1 S,2S)-[2-(4-morpholinyl)-1-(3-(3,4-
dimethoxyphenyl) propoxy)] cyclohexane
,O
/ \
(1R,2R) -[2-[bis(2-methoxyethyl)aminyl]-1-(2-
\ /
naphthen ethoxy)] cyclohexane or (1 S,2S)-[2-[bis(2-
~OMe
methoxyethyl)aminyl]-1-(2-naphthen ethoxy)]
cyclohexane and a mixture of (1R,2R) -[2-[bis(2- OMe
methoxyethyl)aminyl]-1-(2-naphthen ethoxy)] '
cyclohexane and (1S,2S)-[2-[bis(2-
methoxyethyl)aminyl]-1-(2-naphthen ethoxy)]
cyclohexane
.O / C)
( 1 R,2R)-2-(4-morpholinyl)-1-(3,4-dichlorophen
ethoxy) cyclohexane or (1S,2S)-2-(4-morpholinyl)-1- N~ \ CI
~O
(3,4-dichlorophen ethoxy) cyclohexane or a mixture of
( 1 R,2R)-2-(4-morpholinyl)-1-(3,4-dichlorophen
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ethoxy) cyclohexane and (1S,2S)-2-(4-rnorpholinyl)-1-
(3,4-dichlorophen ethoxy) cyclohexane
( 1 R,2R)-2-(3-ketopyrrolidinyl)-1-( 1-naphthenethoxy) O
/
cyclohexane or (1S,2S)-2-(3-ketopyrrolidinyl)-1-(1-
naphthenethoxy) cyclohexane or a mixture of (1R,2R)- N
O
2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)
cyclohexane and (1S,2S)-2-(3-ketopyrrolidinyl)-1-(1-
naphthenethoxy) cyclohexane
.O
( 1 R,2R)-2-( 1-acetylpiperazinyl)-1-(2-naphthenethoxy)
N
cyclohexane or (1S,2S)-2-(1-acetylpiperazinyl)-1-(2- ~N CH3
naphthenethoxy) cyclohexane or a mixture of (1R,2R)-
O
2-(1-acetylpiperazinyl)-1-(2-naphthenethoxy)
cyclohexane and (1S,2S)-2-(1-acetylpiperazinyl)-1-(2-
naphthenethoxy) cyclohexane
CI
(1R,2R)-2-(3-ketopyrrolidinyl)-1-(2,6- W i
dichloro henethox c clohexane or 1 S 2S -2- 3-
p Y) Y ( ~ ) ( N CI
ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy) ~O .HCI
cyclohexane ox a mixture of (1R,2R)-2-(3-
ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)
cyclohexane and (1S,2S)-2-(3-ketopyrrolidinyl)-1-(2,6-
dichlorophenethoxy) cyclohexane
(1R,2R)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1- O
naphthen ethoxy) cyclohexane or (1S,2S)-2-[1,4-dioxa-
7-azaspiro[4.4]non-7-yl]-1-(1-naphthen ethoxy) N O
cyclohexane and a mixture of (1R,2R)-2-[1,4-dioxa-7-
azaspiro[4.4]non-7-yl]-1-(1-naphthen ethoxy)
cyclohexane and (1S,2S)-2-[1,4-dioxa-7-
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azaspiro[4.4]non-7-yl]-1-(1-naplathen ethoxy)
cyclohexane
CF3
(1R,2S)-2-(4-morpholinyl)-1-[(2- '~ i
trifluoromethyl)phenethoxy] cyclohexane
monohydrochloride or ~1O .HCI
(1 S,2R)-2-(4-morpholinyl)-1-[(2-
trifluoromethyl)phenethoxy] cyclohexane
monohydrochloride or a mixture of (1R,2S)-2-(4-
morpholinyl)-1-[(2-trifluoromethyl)phenethoxy]
cyclohexane monohydrochloride and
(1S,2R)-2-(4-morpholinyl)-1-[(2-
trifluoromethyl)phenethoxy] cyclohexane
monohydrochloride
(1 R,2R)-2-(3-ketopyrrolidinyl)-1-[3-
c clohex 1 ro ox c clohexane monoh drochloride
( Y Y )p p Y] y y
.HCI
or (1S,2S)-2-(3-ketopyrrolidinyl)-1-[3-
(cyclohexyl)propoxy) cyclohexane monohydrochloride
or a mixture of (1R,2R)-2-(3-ketopyrrolidinyl)-1-[3-
(cyclohexyl)propoxy] cyclohexane monohydrochloride
and (1S,2S)-2-(3-ketopyrrolidinyl)-1-[3-
(cyclohexyl)propoxy] cyclohexane monohydrochloride
(1 R,2R)-2-(3-acetoxypyrrolidinyl)-1-(1-
naphthenethoxy) cyclohexane monohydrochloride or
(1 S,2S)-2-(3-acetoxypyrrolidinyl)-1-(1-
naphthenethoxy) cyclohexane monohydrochloride or a
mixture of(1R,2R)-2-(3-acetoxypyrrolidinyl)-1-(1-
naphthenethoxy) cyclohexane monohydrochloride and
(1 S,2S)-2-(3-acetoxypyrrolidinyl)-1-(1-
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naphthenethoxy) cyclohexane monohydrochloride
CI w
(1R,2R)-2-(4-mozpholinyl)-1-[(2,6- o ' i
dichlorophenyl)methoxy] cyclohexane a CI
N
monohydrochloride or (1S,2S)-2-(4-morpholinyl)-1- ~O .HCI
[(2,6-dichlorophenyl)methoxy] cyclohexane
monohydrochloride or a mixture of (1R,2R)-2-(4-
morpholinyl)-1-[(2,6-dichlorophenyl)methoxy]
cyclohexane monohydrochloride and (1S,2S)-2-(4-
morpholinyl)-l-[(2,6-dichlorophenyl)methoxy]
cyclohexane monohydrochloride
C
(1R,2R)-2-(3-ketopyrrolidinyl)-1-[(2,6-dichlorophenyl) ~ ~ i
methoxy] cyclohexane monohydrochloride or (1 S,2S)- a CI
N
2-(3-ketopyrrolidinyl)-1-[(2,6-dichlorophenyl)
.HCI
methoxy] cyclohexane monohydrochloride or a mixture
of (1R,2R)-2-(3-ketopyrrolidinyl)-1-[(2,6-
dichlorophenyl) methoxy] cyclohexane ,
monohydrochloride and (1S,2S)-2-(3-ketopyrrolidinyl)-
1-[(2,6-dichlorophenyl) methoxy] cyclohexane
monohydrochloride
CI
(1R,2R)-2-(3-hydroxypyrrolidinyl)-1-(2,6-dichlorophen 'C i
ethoxy) cyclohexane monohydrochlonde or (1S,2S)-2- N CI
(3-hydroxypyrrolidinyl)-1-(2,6-dichlorophen ethoxy) ~~pH .HCI
cyclohexane monohydrochloride or a mixture of
(1R,2R)-2-(3-hydroxypyrrolidinyl)-1-(2,6-dichlorophen
ethoxy) cyclohexane monohydrochloride and (1S,2S)-
2-(3-hydroxypyrrolidinyl)-1-(2,6-dichlorophen ethoxy)
cyclohexane monohydrochloride
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( 1 R,2R)-2-(3-ketopyrrolidinyl)-1-(2,2-diphenylethoxy)
cyclohexane monohydrochloride or (1 S,2S)-2-(3- 'O i
keto olidinyl)-1-(2,2-diphenylethoxy) cyclohexane
p~ N
monohydrochloride or a mixture of (IR,2R)-2-(3- ~O .HCI
ketopyrrolidinyl)-1-(2,2-diphenylethoxy) cyclohexane
monohydrochloride and (1S,2S)-2-(3-ketopyrrolidinyl)-
1-(2,2-diphenylethoxy) cyclohexane
monohydrochloride
CI
(1R,2R)-2-(3-thiazolidinyl)-1-(2,6-dichlorophen O
a ,
ethoxy) cyclohexane monohydrochloride or (1S,2S)-2- N CI
(3-thiazolidinyl)-1-(2,6-dichlorophen ethoxy) ~~ .HCI
cyclohexane monohydrochloride or a mixture of
(1R,2R)-2-(3-thiazolidinyl)-1-(2,6-dichlorophen
ethoxy) cyclohexane monohydrochloride and (1S,2S)-
2-(3-thiazolidinyl)-1-(2,6-dichlorophenethoxy)
cyclohexane monohydrochloride
i
(1R,2S)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)-~ i
cyclohexane monohydrochloride or w
(1 S,2R)-2-(3- N
ketopyrrolidinyl)-1-(1-naphthenethoxy)~O .HCI
cyclohexane
rnonohydrochloride or a mixture of
(1R,2S)-2-(3-
ketopyrrolidinyl)-1-(1-naphthenethoxy)
cyclohexane
monohydrochloride and (1S,2R)-2-(3-ketopyrrolidinyl)-
1-(I-naphthenethoxy)cyclohexane monohydrochloride
.O ~ OMe
(1R,2R)-2-(3-hydroxypyrrolidinyl)-1-(3,4-
N OMe
dimethoxyphenethoxy) cyclohexane .HCI
~~'"~" OH
monohydrochloride or (1S,2S)-2-(3-
hydroxypyrrolidinyl)-I-(3,4-dimethoxyphenethoxy)
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cyclohexane monohydrochloride or a mixture of
(1R,2R)-2-(3-hydroxypyrralidinyl)-1-(3,4-
dimethoxyphenethoxy) cyclohexane
monohydrochloride and (1S,2S)-2-(3-
hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)
cyclohexane monohydrochloride
[0173] Also described here is a composition 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.
[0174] In another version of the aminocyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is a compound or mixture comprising
compounds, or
any solvate thereof, selected from the group consisting of
Structure Chemical name
( 1 R,2R)-2-[(3R)/(3 S )-Hydroxypyrrolidinylj-1-(3,4-
dimethoxyphenethoxy)- cyclohexane or
(1 S,2S)-2-
o [(3R)/(3S)-Hydroxypyrrolidinylj-1-(3,4-dimethoxyphen
.~
ocN3
ethoxy)- cyclohexane or a mixture of
(1R,2R)-2-[(3R)/(3S)-
/ Hydroxypyrrohdmyl]-1-(3,4-dimethoxyphenethoxy)-
3
~'''oH cyclohexane and (1S,2S)-2-[(3R)/(3S)-
~
~ Hydroxypyrrolidinylj-1-(3,4-dimethoxyphenethoxy)-
cyclohexane
(1R,2R)-2-[(3R)-Hydroxypyrrolidinylj-1-(3,4-
,.o dimethoxyphenethoxy)-cyclohexane or
.~ (1S,2S)-2-[(3R)-
ocH3
Hydroxypyrrolidinyi]-1-(3,4-dimethoxyphenethoxy)-
cyclohexane and a mixture of (1R,2R)-2-[(3R)-
3 Hydroxypyrrolidinylj-1-(3,4-dimethoxyphenethoxy)-
cyclohexane and (1S,2S)-2-[(3R)-Hydroxypyrrolidinylj-1-
(3,4-dimethox henethoxy)-cyclohexane
(1 R,2R)-2-[(3 S)-Hydroxypyrrolidinylj-1-(3,4-
o dimethoxyphenethoxy)-cyclohexane or
~ (1S,2S)-2-[(3S)-
ocH3
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-
3 cyclohexane and a mzxture of (1R,2R)-2-[(3S)-
~-''oH Hydroxypyrrolidinylj-1-(3,4-dimethoxyphenethoxy)-
l.
~/ cyclohexane and (1S,2S -2- 3S)-Hydrox
yrrolidinyl -1-
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(3,4-dimethoxyphenethoxy)-cyclohexane
O _-~ OCH3
(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
ocH3 dimethoxyphenethoxy)-cyclohexane
~...,~mOH
OV ~ OCH3
/ (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
..~~°'N~ OCH3 dimethoxyphenethoxy)-cyclohexane
~~OH
O'..~/ ~ OCH3
1R,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
tv ~ oGH3 dimethoxyphenethoxy)-cyclohexane
~...,~mpt..i
O ~ OCFi3
( 1 R,2S)-2-[(3 S)-Hydroxypyrrolidinyl]-1-(3,4-
ocH3 dimethoxyphenethoxy)-cyclohexane
I~OH
,'''\o _ \ oCN3 _.
( 1 S,2R)-2-[(3 R)-Hydroxypyrrolidinyl]-1-(3,4-
,I'~"'N OCH3 dimethoxyphenethoxy) cyclohexane
~.",~~~~OH
,~,v0 ~ OGH3
( 1 S,2R)-2-[(3 S)-Hydroxypyrrolidinyl]-1-(3,4-
ocH3 dimethoxyphenethoxy)-cyclohexane
~~OH
,~,00' ,.~ OCH3 - _
1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
oGH3 dimethoxyphenethoxy)-cyclohexane
I~,.,.,~~~ipH
,,...0 .~ OCH3
( 1 S,2S)-2-[(3 S)-Hydroxypyrrolidinyl]-1-(3,4-
~ oGH3 dimethoxyphenethoxy)-cyclohexane
~~OH
// \~c'~'' (1R,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane or (1S,2R)-2-
rr ocH, [(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen
off ethoxy)-cyclohexane or a mixture of (1R,2S)-2-[(3R)/(3S)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-
cyclohexane and (1S,2R)-2-[(3R)/(3S)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphen ethoxy)-
cyclohexane
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Structure Chemical name
O
/
OCH3
(IR,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
~
OCH dimethox henethox -c clohexane monoh
~~,nlOg drochloride
3 Yh Y) y y
HCI
.
,,w0
~
OCH3
(1 S,2S)-2-I(3R)-Hydroxypyrrolidinyl]-1-(3,4-
N dimethoxyphenethoxy)-cyclohexane monohydrochloride
/
oCH3
~...,~~npH
.HCI
(1R,2R)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane rnonohydrochloride
or (1S,2S)-2-[(3R)/(3S)-Hydxoxypyrrolidinyl]-1-(3,4-
o dimethoxyphenethoxy)-cyclohexane monohydrochloride
~
oCH3
or a mixtuxe of (1R,2R)-2-[(3R)/(3S)-
N~\~OH Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-
.HCI
OCH3
cyclohexane monohydrochloride and (1
S,2S)-2-
[(3R)l(3 S )-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane monohydrochloride
(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane monohydrochloride
ox (1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
oCH3 dimethoxyphenethoxy)-cyclohexane monohydrochloride
/ or a mixture of (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-
\
\N~~""""OH (3,4-dimethoxyphenethoxy)-cyclohexane
.HCI
OCH3
ll
~~.. monohydrochloride and (1S,2S)-2-[(3R)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-
cyclohexane monohydrochloride
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( 1 R,2R)-2-[(3 S)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane monohydrochloride
or (1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
,.o ~ ~ oCH3 dimethoxyphenethoxy)-cyclohexane monohydrochloride
N ~ ocH or a mixture of (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-
~~oH .HCI 3 (3,4-dimethoxyphenethoxy)-cyclohexane
monohydrochloride and (1S,2S)-2-[(3S)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-
cyclohexane monohydrochloride
O ~ OCH3
(1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
.~~""'N,~ ~ oCH3 dimethoxyphenethoxy)-cyclohexane monohydrochloride
rOH .HCI
,~,,~0~ ~ OCH3
(1 S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
N ~ oCH3 dimethoxyphenethoxy) cyclohexane monohydrochloride
L~OH
.HCI
(0175] Also described here is a composition 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.
[0176] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
the ion channel modulating compound is one of the following compounds: (1R,2R)-
2-[(3R)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane free base or any
salt
thereof, or any solvate thereof; (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane free base or any salt thereof, or any solvate
thereof;
(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)-cyclohexane
free base
or any salt thereof, or any solvate thereof; (1 S,2S)-2-[(3S)-
Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethaxy)-cyclohexane free base or any salt thereof, or any solvate
thereof;
(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)-cyclohexane
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rnonohydrochloride, or any solvate thereof; (1R,2R)-2-[(3S)-
Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane monohydrochloride, or any solvate thereof;
(1S,2S)-2-
[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane
monohydrochloride,
or any solvate thereof; or (1 S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)-cyclohexane monohydrochloride, or any solvate thereof.
[0177] In another version of the amino cyclohexyl ether ion channel modulating
compounds,
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 pxotenated 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 amorphous form, and rnay be 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.
AnZinocycloalkyl Etlae~ Ion Claafanel Modulating Conapourads witla 5, 7, and 8
Mernbered Cycloalkyl Rings
[0178] One class of compounds that are ion channel modulating compound
comprise
an aminocycloalkyl ether coxe 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. In one
version the cycloalkyl ring is a 5, 7, or 8 membered ring.
[0179] In one version of the amino cycloalkyl ether ion channel modulating
compounds, the
ion channel modulating compound is a compound having an ether oxygen atom (Q=O
in
formula (IXX~~)) at position 1 of a cycloalkyl ring, and an amine nitrogen
atom at position 2
of the cycloalkyl ring, where the cycloalkyl ring is either cyclopentyl,
cycloheptyl or
cyclooctyl, with other positions numbered in corresponding order as shown
below in structure
(A) for cyclopentane, structure (B) fox cycloheptane, and structure (C) for
cyclooctane:
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\Q ~ -Q ~ -Q
1 N 1 2 1 2
2 ~ 7 3 8 3
4 3 6 4 7 4
6 5
(A) (B) (C)
[0180] 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 traps relationship. In
one version, the
stereochemistry of the amine and ether substituents of the cycloalkyl ring is
either (R,R)-traps
or (S,S)-traps. In another version, the stereochemistry is either (R,S)-cis or
(S,R)-cis.
[0181] In one version of the amino cycloalkyl ether ion channel modulating
compounds, the
ion channel modulating compound is a compound of formula (IXX~~):
Rs
A~ X' _ Q R~
I
N
R~ \R2
R3
n
wherein the substituents A, R~, R2, R3, R4, RS and X are as described above
for formula (1]
and wherein Q is an ether oxygen atom (Q = O in formula (IXXX)) and wherein n
is l, 3 or 4
such that a cyclopentyl, cycloheptyl or cyclooctyl ring is provided.
[0182] Compounds of formula () are cycloalkylamines such as aminocycloalkyl
ethers.
More specifically, these aminocycloalkyl ethers are substituted at position 2
of a cycloalkyl
ring with an amine group NRIRz. The C-1 position is an ether (Q=O in formula
(IXXX)) .
The cycloalkyl ring may also be substituted with additional substituents
(designated as R3 and
R4) as described in more detail below. In formula (IXXX), n is selected from
l, 3 and 4, and
represents a number of carbon atoms such that when n equals 1, the ring shown
in Formula
(IXXX) is a substituted cyclopentane (i.e., a cyclopentyl group), when n
equals 3, the ring
shown in Formula (I~~XX) is a substituted cycloheptane (i.e., a cycloheptyl
group), and when
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n equals 4, the ring shown in Formula (IXXX) is a substituted cyclooctane
(i.e., a cyclooctyl
group). Examples of specific compounds represented by formula (IXXX) are
described
below
[0183] Depending upon the selection of substituents R~ and RZ, the compounds
of formula
(IXXX) may be primary, secondary, or tertiary amines (i.e., both R~ and R2 are
hydrogen,
only one of RI and R2 is hydrogen, or neither of Rl and Rz are hydrogen,
respectively).
Where the amine is tertiary, it may be a cyclic amine. Amine substituents Rl
and R2 may be
independently selected from substituents which include hydrogen, alkyl groups
containing
from one to eight carbon atoms (i.e., C~-CBalkyl), alkoxyalkyl groups
containing from three to
eight carbon atoms (i.e., C3-C$alkoxyalkyl), alkyl groups containing from one
to eight carbon
atoms where one of the carbon atoms is substituted with a hydroxyl group
(i.e., C1-
C$hydroxyalkyl), and aralkyl groups containing from seven to twelve carbon
atoms (i.e.,
C~-Cl2aralkyl).
[0184] Alternatively, RI and R2, when taken together with the nitrogen atom to
which they
are directly attached in formula (IXXX), may form a ring denoted by formula
(I)]:
~'Rl
N R
.- a
wherein the ring of formula (III 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, CI-C3hydroxyalkyl, oxo, C2-
Caacyl,
C1-C3alkyl, C2-C4alkylcarboxy, C1-C3alkoxy, C~-CZOalkanoyloxy, or may be
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 C3-CBCarbocyclic
ring, and any
one or more of the additional nitrogen ring atoms may be substituted with
substituents
selected from hydrogen, C1-C6alkyl, Cz-C4acyl, C2-C~hydroxyalkyl and C3-
C$alkoxyalkyl.
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Examples of substituents containing a fused ring system include the
perhydroindolyl and
1,2,3,4-tetrahydroisoquinolinyl groups.
[0185] In connection with the ring of formula (IIJ, any two adjacent ring
atoms may be joined
together by single or double bonds. Thus, the ring of formula (II) may be
saturated or
unsaturated, and an unsaturated ring may contain one, or more than one, sites
of unsaturation.
In other words, the ring of formula (In may contain one or more double bonds,
it being
understood, however, that the unsaturated ring of formula (IIJ is chemically
stable.
[0186] Alternatively, R~ and RZ, when taken together with the 2-amino nitrogen
of formula
(IXXX), may complete a bicyclic ring. Bicyclic rings include, for example,
3-azabicyclo[3.2.2]nonane, 2-azabicyclo[2.2.2]octane,3-
azabicyclo[3.1.0]hexane, and
3-azabicyclo[3.2.0]heptane. For these derivatives, the C-2 substituents of the
cycloalkyl
ethers of formula (I) are the following groups: 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.
[0187] Preferably for formula (II], RI and R2, when taken together, contain
only a single
heteroatom. Preferred heteroatoms include nitrogen, oxygen and sulfur. An
example of a
ring in which Rl and RZ together include an oxygen heteroatom is the
morpholinyl group. An
example of a ring where Rl and Ra together include a second nitrogen
heteroatom is the
piperazinyl group.
[0188] Cycloalkyl substituents R3 and R4 may be independently attached to any
of the ring
positions except positions. l and 2 (e.g.~ both R3 and R4 may be attached to
the same ring
position or each attached to different ring positions). R3 and R4 are
independently selected
from hydrogen, hydroxy, C1-C6alkyl, and CI-C6alkoxy, and, when both R3 and R4
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 substituents contain either a single oxygen or a single
sulfur ring atom.
[0189] Depending upon the identity of X, the ether sidechain, -CH(RS)-X-A, in
formula
(Z~~XX) may take several forms. For example, a compound of formula (IXXX) may
have X
as a -C(Rb,Rl4)-Y- group, where Y may be any of a direct bond, an oxygen atom
(O), a sulfur
atom (S) or a C~-C4alkylene group. R6 and RI4 axe independently selected from
hydrogen,
C1-C6alkyl, aryl and benzyl, or R6 and R14, when taken together with the
carbon to which they
are attached, may form a spiro C3-Cscycloalkyl. Thus, compounds of the
invention include
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compounds of formula (I~~XX) where R6 and R14 are hydrogen and Y is a direct
bond, such
that X may be CH2.
[0190] Alternatively, X may be an alkenylene moiety, e.g., a cis-or traps-
alkenylene moiety,
C(R13)=CH, where RI3 may be any of hydrogen, CI-C6alkyl, C3-C$cycloalkyl, aryl
or benzyl.
For compounds of formula (IXXX) where X is an alkenylene moiety, X is
preferably a
traps-alkenylene moiety.
(0191] Alternatively, X may be a direct bond. Independent of the selections
for A, X and
other variables, RS is selected from hydrogen, Ci-C6alkyl, aryl and benzyl.
[0192] Ether sidechain component A is generally a hydrophobic moiety.
Typically, 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, ox sulfur ring atoms. Suitable hydrocarbons are CS-Cl2alkyl and C3-
Ci3carbocyclic
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 (III), (IV), (V), (VI), (VI)], or (VIII) respectively.
[0193] A suitable "A" group within the compounds of the present invention is a
phenyl ring
represented by formula (~:
R~
R8
where R~, Rg and R9 are independently selected from bromine, chlorine,
fluorine, carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl,
C2-C~alkanoyloxy, C1-C6alkyl, Cl-C6alkoxy, C2-C7alkoxycarbonyl, Cl-
C6thioalkyl, aryl and
N(R15,R16) where Rls and R16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and CI-C6alkyl.
(0194] For compounds of formula (IXXX) where X is a direct bond or CH2, at
least one of
R7, R$ and R9 is preferably selected from amine (-NR~SR16, where Rls and Rlb
are
independently hydrogen, acetyl, methanesulfonyl, and C~-C6alkyl), bromine,
chlorine,
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fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, nitro, trifluoromethyl,
CZ-C~alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C~alkylcarbonyl, C~-C6thioalkyl
or aryl
groups. For compounds of formula (I) when X is CH=CH, and R3 and R4 are
hydrogen, at
least one of R~, R$ and R9 is preferably a substituent other than hydrogen. "
[0195] Other suitable "A" groups in compounds of the present invention are 1-
naphthyl
groups as represented by formula (1~:
/ \
Rlo Rii
\ /
where Rlo and R11 are independently selected from bromine, chlorine, fluorine,
carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl,
C2-C~alkanoyloxy, C1-Cbalkyl, CI-C6alkoxy, CZ-C~alkoxycarbonyl, C1-
C6thioalkyl, and
N(R~S,R16) where Rls and RI6 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C~-C6alkyl.
[0196] Other suitable "A" groups in compounds of the present invention are 2-
naphthyl group
as represented by formula (V):
/ \ H
Rl o R1 i
\ /
(V)
where R1o and Ril are independently selected from bromine, chlorine, fluorine,
carboxy,
hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluorornethyl,
Ca-C~alkanoyloxy, C~-C6alkyl, C1-C6alkoxy, CZ-C~alkoxycarbonyl, C1-
C6thioalkyl, and
N(RIS,Ri6) where R~5 and Ri6 are independently selected from hydrogen, acetyl,
methanesulfonyl, and CI-C6alkyl, as defined above.
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[0197j Other suitable "A" groups in compounds of the present invention axe
aromatic groups
represented by formula (VI):
. . R,a \ - Z~
(~
where Riz is selected from bromine, chlorine, fluorine, carboxy, hydrogen,
hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, CZ-
C~alkanoyloxy,
CI-C6alkyl, CI-C6alkoxy, CZ-C~alkoxycarbonyl, C1-Cbthioalkyl, and N(RlS,Ris)
where R~5
and Rt6 axe independently selected from hydrogen, acetyl, methanesulfonyl, and
CI-C6alkyl; '
and Z is selected from CH, CHZ, 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 Rl~
when Z is N,
and RI~ is selected from hydrogen, Cl-C6alkyl, C3-C$cycloalkyl, aryl and
benzyl.
(0198] The aryl groups of formula (VI) are derivatives of indene, indole,
benzofuran, and
thianaphthene when Z is methylene, nitrogen, oxygen, and sulfur, respectively.
Preferred
heterocyclic groups of formula (Vn include indole where Z is NH, benzofuran
where Z is O,
and thianaphthene where Z is S. As described below, in a preferred embodiment,
Z is O, S or
N-Rig, and in a particularly preferred embodiment Z is O or S.
(0199] Another suitable "A" group in compounds of the present invention are
acenaphthyl
groups as represented by formula (VIA:
/ \
\ /
[0200] Still another suitable "A" group in compounds of the present invention
is the fluorenyl
group represented by formula (VILA:
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CA 02524034 2005-11-O1
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w i
/ \
(~
[0201] Preferably, ether sidechain component A is an acenapthyl or fluorenyl
group only
when X is a direct bond or CH2. In othex variations, the acenaphthyl group is
a 1-acenaphthyl
group, and the fluorenyl group is a 9-fluorenyl group.
[0202] In another variation of (IXXX), X is (CH2)-Y. For these variations, Y
is a direct bond,
an oxygen atom, or a sulfur atom. In a particular variation, Y is a direct
bond or an oxygen
atom. In another variation, Y is a direct bond and X is C(R.g,Rl4), where R.6
and R» are as
dei~xned above. In another variation, X is C(RI3)=CH, and R» is a hydrogen
atom. For these
variations, R3 and R4 are preferably independently attached to the cycloalkyl
ring at the 4- or
5- positions.
(0203] Ion channel modulating compounds of formula (IXXX) may be provided,
wherein:
independently at each occurrence,
n is selected from l, 3 and 4;
Q is either O (oxygen) or -O-C(O);
X is selected from a direct bond, -C(R.6,RI4)-Y- and -C(R13)=CH-;
Y is selected from a direct bond, O, S and Cl-C4alkylene;
R~3 is selected from hydrogen, C1-C6alkyl, Cs-C$cycloalkyl, aryl and benzyl;
R~~ and R2 are independently selected from hydrogen, Ci-C$alkyl,
C3-C$alkoxyalkyl, Ci-Cahydroxyalkyl, and C~-ClZaralkyl; or
Rl and Rz are independently selected from C3-C$alkoxyalkyl, C1-
CBhydroxyalkyl, and C~-Cl2aralkyl; or
Rl and RZ are taken together with the nitrogen atom to which they are directly
attached in formula (IXXX) to form a ring denoted by formula (II):
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N
~'Rl
~- Ra
wherein the ring of formula (II) is formed from the nitrogen as shown as well
as three to nine
additional ring atoms independently selected from carbon, nitrogen, oxygen,
and sulfur;
where any two adjacent ring atoms may be joined together by single or double
bonds, and
where any one or more of the additional carbon ring atoms may bear one or two
substituents
selected from hydrogen, hydroxyl, C1-C3hydroxyalkyl, oxo, C2-C4acyl, CI-
C3alkyl,
C2-C4alkylcarboxy, Cl-C3alkoxy, CI-C2oalkanoyloxy, or may form a spiro five-
or
six-membered heterocyclic ring containing one or two heteroatoms selected from
oxygen and
sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-
CBCarbocyclic
ring, and any one or more of the additional nitrogen ring atoms may bear
substitue~ts selected
from hydrogen, Ci-C6alkyl, C2-C4acyl, Cz,-C4hydroxyalkyl and C3-C$alkoxyalkyl;
or
Rl and RZ are taken together with the nitrogen atom to which they are directly
attached in formula (IXXX) 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-
azabicycloj3.1.0]hexan-3-yl
and 3-azabicyclo[3.2.0)heptan-3-yl;
R3 and R4 are independently attached to the cycloalkyl ring shown in formula
(IXXX) at other than the l and 2 positions and are independently selected from
hydrogen,
hydroxyl, CI-C6alkyl and C1-C6alkoxy, and, when both R3 and R4 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;
R5, R6 and Ri4 are independently selected from hydrogen, Cl-C6alkyl, aryl and
benzyl, or R6 and RI4, when taken together with the carbon to which they are
attached, may
form a spiro C3-Cscycloalkyl;
A is selected from CS-C~Zalkyl, a C3-Ci3carbocyclic ring, and ring systems
selected from formulae (III), (IVJ, (~, (VI), (VII) and (VIIn:
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R~
R$
where R~, R$ and R9 are independently ~ selected from bromine, chlorine,
fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl,
trifluoromethyl, C2-C~alkanoyloxy, C1-C6alkyl, C~-C6alkoxy, CZ-
C~alkoxycarbonyl,
C~-C6thioalkyl, aryl and N(Rl5,Ri6) where R~5 and R16 are independently
selected from
hydrogen, acetyl, methanesulfonyl and CI-Cbalkyl;
/ \
Rlo \ / Rn Rto Rn
and ~ /
(
where Rlo and R11 are independently selected from bromine, chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro,
sulfamyl,
trifluoromethyl, C2-C~alkanoyloxy, CI-C6alkyl, C1; C6alkoxy, CZ-
C~alkoxycarbonyl,
C1-C6thioalkyl, and N(R15,R16) where Rls and R~6 are independently selected
from hydrogen,
acetyl, methanesulfonyl, and C1-C6alkyl;
R12 ~ Z~.. o
where Rl2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen,
hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl,
C~-C~alkanoyloxy, C1-C6alkyl, CI-C6alkoxy, CZ-C~alkoxycarbonyl, C1-
C6thioalkyl, and
N(RIS,R~6) where R~5 and RI6 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C~-C6alkyl; and Z is selected from CH, CH2, O, N and S,
where Z may
be directly bonded to "X"' as shown in formula (when Z is CH or N, or Z may be
directly bonded to R» when Z is N, and Rl~ is selected from hydrogen, Cl-
C6alkyl,
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C3-Cgcycloalkyl, aryl and benzyl;
/ \
\ ~ / ~
a)
including isolated enantiomeric, diastereomeric and geometric isomers thereof;
In another version of the amino cycloalkyl ether ion channel modulating
compounds,
the ion channel modulating compound is one of the following compounds or
mixtures of
compounds.
(1R,2R) -2-(4-Morpholinyl)-1-(2-naphthalenethoxy)
cyclopentane monohydrochloride or (1S,2S)-2-(4-
Morpholinyl)-1-(2-naphthalenethoxy) cyclopentane
monohydrochloride or a mixture of ( 1 R,2R) -2-(4-
Morpholinyl)-1-(2-na~phthalenethoxy) cyclopentane
monohydrochloride and (1S,2S)-2-(4-Morpholinyl)-1-
(2-naphthalenethoxy) cyclopentane
monohydrochloride
(1R,2R) -2-(3-Ketopyrrolidinyl)-1-(2,6- 1
dichlorophenethoxy)cyclopentane monohydrochloride /
or (1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-dichlorophen
' Cl
ethoxy) cyclopentane monohydrochloride or a mixture
of (1R,2R) -2-(3-Ketopyrrolidinyl)-1-(2,6-
N
dichlorophenethoxy) cyclopentane monohydrochloride , ~O ~ HCl
and (1S,2S)-2-(3-Ketopyrrolidinyl)-1-(2,6-
dichlorophen ethoxy) cyclopentane
monohydrochloride
.HCI
[0204] In another version of the amino cycloalkyl ether ion channel modulating
compounds,
the ion channel modulating compound is a protenated version of any of the
amino cycloalkyl
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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 amorphous form, and may be 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.
Geizeral DescriptioTZ oflon Channellllodulatifa~ Com op unds
[0205] Generally, 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.
[0206] In another version, 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 currents. Ion channel modulating compounds may block
cardiac curt~ents
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 morphology, premature action potentials, high heart rates and may
also include
increased variability in the time between action potentials and an increase in
cardiac milieu
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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 currents
or cardiac early repolarizing currents. An ion channel modulating compound may
inhibit
multiple cardiac ionic currents. An ion channel modulating compound may be
used to treat
or prevent arrhythmic, including ventricular or atrial arrhythmia,
particularly atrial
fibrillation. '
[0207) 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
arrhythmogenic
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
arrhythmogenic
substrate is present in the heart; and/or block cardiac early repolarizing
currents and cardiac
sodium currents from extracellular loci in cardiac cells.
[0208) In one variation, the cardiac early repolarizing currents referred to
above comprise
ionic currents which activate rapidly after depolarization of membrane voltage
and which
effect repolarization of the cell. The early repolarizing currents may
comprise the cardiac
transient outward potassium current (Ito) and/or the ultrarapid delay
rectifier current (IKur).
The cardiac transient outward potassium current (lto) andlor the ultrarapid
delay rectifier
current (I~"r) may comprise at least one of the Kv4.2, Kv4.3, Kv2.l, Kvl.4 and
Kvl.S
currents.
[0209] 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). For 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 arrhythmogenic substrate in the heart as described above
due to the
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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.
(0210] Particular ion channel modulating compounds have structural
characteristics that may
be determined by various physical methods, such as single crystal X-ray
crystallography. For
instance, some ion channel modulating compounds comprise a cycloalkane ring
and .
substituents J and K as shown below in structure T, wherein the relative
positions of J and K
provide a "C" shaped angle and wherein n = l, 2, 3 or 4.
J "C" angle
,
n
(T)
(0211] Typically, one of J and K comprises a hydrophobic moiety, such as but
not limited to
a moiety comprising alkyl and/or aryl moieties. In one variation, 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. Typically, one of J and K 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 andlor a hydroxyl moiety. In one
variation, one of J and
K comprises a nitrogen containing moiety substituted with a hydroxyl moiety or
the like, such
as a pyrrolidinyl moiety. In a particular variation of structure T, n = 2, J
comprises a aromatic
moiety and K comprises a nitrogen containing moiety substituted with a
hydroxyl moiety or
the like. The cycloalkane ring may be optionally substituted. In one version,
the cycloalkane
ring may be replaced by a structural moiety imparting rigidity to the relative
positions of the J
and K groups. For example if the J and K groups are attached to atoms L and M
that are
directly bonded to each other, any group that does not allow substantial
rotation about the
bond between atoms L and M can impart rigidity to the relative positions of
the J and K
groups. For example, the ion channel modulating compound may be a compound of
formula
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P~ ~'s'~.,, J
R~ Mgt' K
where J and I~ axe as described above and groups P and R are moieties such
that there is not
substantial rotation about the L-M bond. In one example P and Q taken together
form a
cyclic moiety that prevents substantial rotation about the L-M bond.
[0212] In one version, 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 substituted
or
unsubstituted cycloalkyl ring. The amino substituted cycloalkane ring may be
an
aminocyclohexyl ring and may be further substituted with one or more
additional moieties. In
one version, the amino substituted cycloalkane ring is further substituted
with an ether
moiety. In some instances, the ion channel modulating compound comprises an
aminocyclohexyl ring that is further substituted with an ether moiety.
[0213] In another, 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 amorphous form, and may be 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
METHODS OF MAI~.ING ANTIARRHYTHMIC COMPOUNDS
[02.4] Methods that may be used to synthesize the ion channel modulating
compounds
described in this section are described in PCT/US03/34655 (filed October 31,
2003), US
60/516,248 (filed October 31, 2003), WO 99150225, and WO 00/47547 each of
which is
incorporated herein by reference in its entirety.
[0215] In one method, illustrated in Figure l, compounds are prepared by a
Williamson ether
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CA 02524034 2005-11-O1
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synthesis (Feuer, H.; Hooz, J. Methods of Formation of the Ether Linkage. In
Patai, Wiley:
New York, 1967; pp 445-492) between an activated form of aminoalcohol 4R with
the
alkoxide of 3,4-dimethoxyphenethyl alcohol in a polar solvent such as
dimethoxyethane
(ethylene glycol dimethyl ether) (DME) (Figure 1) that provided the
corresponding
aminoether 5R in high yield. Subsequent resolution of the diastereomers such
as by
chromatographic separation (e.g. HPLC) to afford SRRR arid SSSR followed by
hydrogenolysis provided compound 1 and compound 2 respectively.
[0216) (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane free
base and the corresponding monohydrochloride (compound 6) and (1S,2S)-2-[(3S)-
hydroxy-
pyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane free base and the
corresponding
monohydrochloride (compound 7) are obtained using a similar synthetic sequence
but starting
with 3-(S)-hydroxypyrrolidine.
[0217) Hydrogenolysis of (1R,2R)/(1S,2S)-2-[(3R)-benzyloxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane (SR) provided (1R,2R)l(1S,2S)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane free base and the
corresponding rnonohydrochloride (compound 4). Similarly, starting with 3-(S)-
hydroxypyrrolidine instead of 3-(R)-hydroxypyrrolidine and following the same
synthetic
sequence will~afford (1R,2R)/(1S,2S)-2-[(3S)-benzyloxypyrrolidinyl~-1-(3,4-
dimethoxyphenethoxy)cyclohexane. The latter on hydrogenolysis will provide
(1R,2R)/(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane free
base and the corresponding monohydrochloride (compound 5). (1R,2R)/(1S,2S)-2-
[(3R)l(3S)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane free base and the
corresponding monohydrochloride (compound 3) can also be synthesized by
similar process
by starting with racemic 3- hydroxypyrrolidine.
FORMULATIONS, ROUTES OF ADMINISTRATION AND DOSAGE FORMS
[0218] In this section are described general formulations, routes of
administration, and
dosage forms that may be used in the methods described in this patent.
Specific formulations,
routes of administration, and dosage forms that may be used for treating,
preventing, and
postponing onset of arrhythmia are described in more detail in the Method of
Treating
Arrhythmia and Method of Preventing or Postponing Onset of Arrhythmia
sections.
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Formulatiort and routes o~'administration
(0219) 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. As used herein "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.
Dosa a Forms and Dosage Amounts and Dosage Fr~uenc~
(0220] In general, the amount of the ion channel modulating compound present
in a
composition depends hater 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.
[0221) The dosage frequency also depends on the disease or condition to be
treated andlor
prevented, amount or concentration of the ion channel modulating compound, the
specific
composition used, the route of administration, and may incorporate subject-
specific variation
including, but not limited to age, weight, gender, genetic background, arid
overall health. For
example, a nasal formulation may be administered.once daily e.g. in order to
achieve a
relatively fast onset of the therapeutic effect, or it may be administered
more often. The same
criteria for selecting dosage frequency applies to other dosage forms
including but not limited
to a plain tablet composition, a buccal composition, a rectal composition, an
oral
composition, a topical composition, an ocular composition, or other
compositions.
[0222] 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.
[0223) A controlled release formulation as described herein may allow dosage
once, twice, or
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CA 02524034 2005-11-O1
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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.
(0224] Typically, 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.
[0225] 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.
[0226] 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.
[0227] A physician or veterinarian having ordinary skill in the art can
readily determine and
prescribe the effective amount of the pharmaceutical composition required. For
example, 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.
(0228] In general, 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 (1V), nasal forms, sublingual and metered
dose inhaler
forms. Generally, intravenous and oral forms of the ion channel modulating
compound for a
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subject will range from about 0.1 to about 50 mg per kilogram of body weight
per day. For
ion channel modulating compound such as the aminocyclohexyl ether compound
(1R, 2R)-2-
[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride, a
therapeutic dosage for the intravenous form may be from about 0.1 ,to about 10
mg per
kilogram. Another suitable dosage of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-
(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride for the intravenous form may
be from
about 2 to about 5 mg per kilogram. For ion channel modulating compound such
as the
arilinocyclohexyl ether compound (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride,.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 (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride for oral administration may
be from
about 300 to about 900 mg tablets or capsules b.i.d.
(0229] Intranasal formulations and patch formulations are also preferred
forms. Generally,
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.
[0230] 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.
[0231] 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.
Routes of adfninistration
(0232] 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,
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intraperitoneal, intranasal, enteral, topical, sublingual, buccal, gingival,
palatal or rectal
means.
[0233] Typically, the ion channel modulating compound is given in forms
suitable for each
administration route. For example, 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.
(0234] The phrases "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, intraarticulax, subcapsular, subarachnoid,
intraspinal, and
intrasternal injection and infusion.
[0235] The phrases "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). The phrases "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).
[0236] Regardless of the route of 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.
[0237] The phrase "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.
[0238] The ion channel modulating compounds can be administered alone or in
admixtures
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with pharmaceutically acceptable andlor sterile carriers arid 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
[0239] Formulations of ion channel modulating compounds can be formulated in
any manner
suitable for a desired delivery route. Typically, 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 andlor physiological milieu of the ion channel modulating
compound.
[0240] 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 ox
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.
[0241] 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,
dxenches
(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. However, in certain embodiments the subject compounds may be
simply
dissolved or suspended in sterile water.
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(0242] 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 mixtures thereof. The optirnurn concentration of the
ion channel
modulating compound in the chosen medium can be determined empirically,
according to
procedures well known in the art. As used herein, "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. The use of a
biologically
acceptable medium for pharmaceutically active substances is known in the art.
Suitable
biologically acceptable media and their formulation are described, for
example, in the most
recent version of Remington's Pharmaceutical Sciences (Remington's
Pharmaceutical
Sciences. Mack Publishing Company, Easton, Pa., USA 1985).
(0243] 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. As used herein, "bioavailability" refers to
the effect,
availability and persistence of the ion channel modulating..compound after
being administered
to a subject.
[0244] 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. Some examples of
materials which can
serve as pharmaceutically acceptable Garners 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
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ethyl laurate; agar; buffering agents, such as magnesium hydroxide and
aluminum hydroxide;
alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol; phosphate
buffer solutions; and any other compatible substances employed in
pharmaceutical
formulations.
[0245] 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, fox 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. Other salt forms include hydrochloride,
hydrobromide,
hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate,
phosphate or acid
phosphate, acetate, maleate, fumarate, lactate, tarixate, L- tartrate,
citrate, gluconate,
benzenesulphonate (besylate), p-toluenesulphonate (tosylate),
methanesulphonate (mesylate),
esylate, succinate, salicylate, nitrate, sulfate, etc.
[0246] Formulations of the ion channel modulating compounds can also include
wetting
agents; emulsifiers and lubricants such as sodium lauryl sulfate and magnesium
steaxate;
coloring agents; release agents; coating agents; sweetening, flavoring, and/or
perfuming
agents; preservatives; and antioxidants.
[0247] Examples of pharmaceutically acceptable 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.
[0248] Formulations of ion channel modulating compounds may also incorporate
buffering
agents and/or salts to aid absorption 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
incorporated in the
formulation. Formulations of ion channel modulating compounds may also contain
opacifying agents.
[0249] The formulations of ion channel modulating compounds may be presented
in unit
dosage form and may be prepared by any methods known in the art. The amount of
ion
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channel modulating compound that can be combined with a carrier material to
produce a
single dosage form may vary. For example, the amount of ion channel modulating
compound
in a given formulation may depend upon the host being treated and/or the
pat~icular 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. .
[0250] Methods of preparing these formulations include the step of bringing
into association
an. ion channel modulating compound with the carrier andlor 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 carriers,
or both, and then
shaping the product.
[0251] Formulations of the ion channel modulating compound suitable for oral
administration may be 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); and/or as
mouth rinses or washes and the like; or as a bolus, electuary or paste.
[0252] 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 pyrrolidone, sucrose andlor 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;
absorption
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. The formulation may also include
buffering
agents, particularly when the ion channel modulating compound is in the form
of a capsule,
tablet or pill.
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[0253] 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.
[0254] 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 mixture of powdered ion channel
modulating
compound moistened with an inert liquid diluent.
[0255) Solid formulations of ion channel modulating compounds described
herein, such as
dragees, capsules, pills and granules, 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. Thus, solid formulations could include any material that could
provide a desired
release proEle of the ion channel modulating compound, including but not
limited to
hydroxypropylmethyl cellulose in varying proportions, or other polymer
matrices, liposomes
and/or microspheres.
[0256] 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. Examples
of
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.
[0257] Coated or encapsulating formulations of ion channel modulating
compounds may also
be formulated to deliver pulsatile, sustained, or extended release. For
example one method of
pulsatile release could be achieved by layering multiple coatings of ion
channel modulating
compound, or by incorporating the ion channel modulating compound within
different
regions of the formulation having different release times.
[0258] Other example of methods and materials for pulsatile delivery include,
but are not
limited to those described in the patent documents listed below and the
patents and
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publications referenced therein, all of which are incorporated by reference
herein.
IJS Patent No.
6,645,524 Oral pharmaceutical dosage forms for pulsatile deliverof an
antiarrhythmic went
6.635,277 Composition for ~ulsatile delivery of diltiazem and process of
manufacture
6,627,223 Timed pulsatile dru d~'-elivery systems
6.607y751Controlled release delivery device for pharmaceutical
agents
inco orp rating microbial polysaccharide~nm
6,596,314Conixolled release liquid active a~2ent formulation
dosage forms
6,555 Pharmaceutical dosaeye form for pulsatile delivery
136 of methylphenidate
6,500,457Oral pharmaceutical dosage forms for pulsatile
delivery of an
antiarrhythmic went
6,461,331Device and method for infusion of small molecule
insulin mimetic
materials
6,387,037Implantable heart assist system and method of
applyin~same
6372,254Press coated, pulsatile drug delivery system
suitable for oral
administration
6,342,249Controlled release liquid active went formulation
dosage forms
6,340,476Pharmaceutical dosage form for pulsatile deliverof
rnethylt~henidate
6,312,409Device for generating a ~ulsatile fluid dru
flow
6,217,904Pharmaceutical dosage form for pulsatile deliverof
d-threo-
methylphenidate and a second CNS stimulant
6,214,377Melatonin for the production of a peroral pulsatile
form of medication
6,117,450Method of makin~a ~erorally administered solid
drug with controlled
effectiye ineredient deliver
6,080,721Pulmonary delivery of active fragments of parathyroid
hormone
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5,965.521 Pulsatile delivery of leptin receptor li a~ nds
5.,840,329 Pulsatile drug delivery s sy tem
5,814,607 Pulmonary delivery of active fragments of parathyroid hormone
5,716,318 Method of treating cardiac arrest and apparatus for same
607.915 Pulmonary delivery_of active fragtrrents of parathyroid hormone
5,456,679 Delivery devices with pulsatile effect
5,318.558 Osmotically driven delivery device with expandable orifice for
pulsatile
delivery efFect
4,698.062 Medical device for pulsatile transdermal deliver~t of biolo~ically
active
a ents
4,687,423 Electrochemically-driven ~ulsatile drug dispenser
4,525,165 Fluid handling system for medication infusion system
US Pat.
Application
No.
20030203029Controlled release liguid active a!;ent formulation
dosage forms
20030194439Pharmaceutical dosa~-e form for uulsatile delivery
of methylnhenidate
20030171282Pulmonary delivery of active fragments of parathyroid
hormone
20030170181Method for ~axeventin~ abuse of methylphenidate
20030003149Composition for pulsatile deliver<r of diltiazem
and process of manufacture
20020098232Oral pharmaceutical dosage forms for pulsatile
delivery of an
antiarrhythmic agent
20020086055Controlled release liauid active went formulation
dosage forms
20020082680Expandable medical device for delivery of beneficial
went
20020058061Pharmaceutical dosage form for pulsatile delivery
of methylphenidate
20020007139Medical infusion and aspiration system
20010046964Timed pulsatile drug delivery s std
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[0259] Liquid dosage formulations for oral administration of the ion channel
modulating
compounds may include pharmaceutically acceptable emulsions, rnicroemulsions,
solutions,
suspensions, syrups and elixirs. In addition to the ion channel modulating
compound, 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, corn, germ,
olive, castor and sesame oils); glycerol; tetrahydrofuryl alcohol;
polyethylene glycols; and
fatty acid esters of sorbitan, and mixtures thereof.
[0260] The ion channel modulating compound may also be formulated as a
suspension.
Suspensions of the ion channel modulating compound may include suspending
agents.
Examples of 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.
[0261] Formulations of the ion channel modulating compound for rectal or
vaginal
administration may be presented as a suppository. Suppository fornlulations
may be prepared
by mixing one or more ion channel modulating compounds with one or more
suitable
nonirritating excipients ox Garners. Suitable carriers 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.
[U262] 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.
[0263] 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 Garner, and with any
preservatives,
bufFers, or propellants which may be required.
[0264] Powders and sprays may contain, in addition to an ion channel
modulating compound,
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excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium
silicates and
polyarnide powder, or mixtures of these substances. Sprays may contain
customary
propellants, such as chlorofluorohydrocarbons and volatile unsubstituted
hydrocarbons, such
as butane and propane.
[0265] 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.
Absorption enhancers may also be used to increase the flux of the compound
across the skin.
The rate of flux may be 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.
[0266] Ophthalmic formulations of the ion channel modulating compound include,
but are
not limited to, eye ointments, powders, solutions and the like.
[0267] 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.
[0268] 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. Examples of biodegradable polymers include, but are
not limited to
polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The xatio
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
cap also be prepared by entrapping the drug in liposomes or microemulsions.
[0269] Proper fluidity of liquid, suspension and other formulations of the ion
channel
modulating compounds can be maintained by the use of coating materials such as
lecithin; by
the maintenance of the required particle size in the case of dispersions; or
by the use of
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surfactants.
[0270] 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.
[0271] Formulations of the ion channel modulating compound may also be
sterilized by, for
example, by filtration through a bacteria-retaining filter, or by
incorporating 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.
[0272] Formulations of the ion channel modulating compounds may also include
isotonic
agents such as sugars, sodium chloride, and the like.
[0273] 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 absorption 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 amorphous material having poor Water solubility.
The rate of
absorption 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
absorption of a parenterally administered drug foam can be accomplished by
dissolving or
suspending the drug in an oil vehicle. Prolonged absorption formulations for
injection can
include agents which delay absorption including but not limited to aluminum
monostearate
and gelatin.
(0274] 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.
Immediate Release and Controlled Release formulations
[0275] The ion channel modulating compounds described herein may be formulated
as
immediate release (IR) or controlled release (CR) tablets.
(0276] In one version, the ion channel modulating compound formulation
contains (1R,2R)-
2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-dirnethoxyphenethoxy) cyclohexane
monohydrochloride
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(CzoH31N04.HC1). This compound is orally bioavailable in humans and animals
(dog, rat and
monkey). The drug is rapidly absorbed, and has a linear PK in humans following
a 10-minute
infusion. The half life of the drug in healthy volunteers has been shown to be
approximately
2 hours compared to 3-4 hours in patients with recent onset AF.
[0277] The drug is highly soluble in citrate solution (143 mg/mL), and has a
pH of 3.2 in
water, and a pKa of 8.32. It is anhydrous, and is stable under long term and
accelerated
conditions (TCH). Both IR 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 IR tablets may have approximately the same
weight and
appearance.
a. Continuous Release tablets of (IR,2R)-2-((3R)-HydroxypyrrolidirzylJ-1-(3,4-
dizyzetlzoxyplzezzethoxy) cyclohexarze monohydrochloride (C2oH3~NO4.HCl)
CR tablets may be made by incorporating the drug within a matrix systems,
including but not
limited to: a hydrophilic matrix system, a hydrophobic (plastic matrix
system), a
hydrophiliclhydrophobic matrix system, a fat/wax system, and a film-coated
particulate
system.
[0278] 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.
(0279] Hydrophilic/ hydrophobic matrix systems utilize a combination of
hydrophilic and
hydrophobic polymers that forms a soluble/insoluble matrix in which the drug
is embedded.
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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.
[0280] In Fat-wax matrix systems, the drug is incorporated in a hot melt of a
fat-wax matrix,
solidified sized and compressed with appropriate tablet ingredients.
Controlled xelease 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.
[0281] 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.
(0282] Excipients that may be used for the above CR matrix systems are listed
in tables 1 to 5
below. Outlined are the chemical and brand names, compendial status, function,
and range of
use levels.
Table 1: Excipients for Hydrophilic Matrix System
Item Compendia(
F~ccipient Function
# Status Low High
1. Methocel K4M USP Hydrophilic 10.040.0
(CR Grade) polymer
2. Hydroxyprapyl USP/EP/JP Hydrophilic 10.040.0
Cellulose polymer
3. Methocel E4M USA Hydrophobic 10.440.0
Premium polymer
(CR Grade)
4. Sodium carboxymethylUSP Hydrophobic 10.040.0
cellulose polymer
5. Hydroxyethyl USP/EP/JP Hydrophilic 10.040.0
Cellulose polymer
6. Polyvinyl pyrrolidone~ USP Hydrophilic 5.0 10.0
Polymerlf3inder
7. Lactose (Fast USPIEPIJP Filler/Diluent20.060.0
Flo)
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8. Microcrystalline USP/EP/JP Filler/Diluent16.730.0
Cellulose
(Avicel)
9. Calcium PhosphateUSP-NF Filler/Diluent16.733.3
Dibasic (Emcompress)
10. Colloidal SiliconUSP/EP/JP Glidant 0.5 2.0
Dioxide
11. Magnesium StearateUSP/EP/JP Lubricant 0.5 1.0
(Non-Bovine)
12. Stearic Acid USP/EP Lubricant 0.5 2.0
Table 2: Excipients for Hydrophobic Matrix System
Item Compendia)
Excipient Function
# Status Low High
1. Ethyl Cellulose USP-NF Hydrophobic 20.040.00
(Ethocel) polymer
2. Eudragit RSPO USP-NF Hydrophobic 20.040.00
polymer
3. Eudragit S-100 USP-NF Hydrophobic 20.040.00
polymer
4. Kollidon SR USP-NF Hydrophobic 20.040.00
polymer
5. Lactose (Fast USP/EP/JP FiIIer/Diluent 20.060.0
Flo)
6. Microcrystalline USN/EP/JP Filler/Diluent 16.730.0
Cellulose
(Avicel)
7. Calcium PhosphateUSP-NF Filler/Diluent 16.733.3
Dibasic (Emcompress)
8. Colloidal SiliconUSP/EP/JP Glidant 0.5 2.0
Dioxide
9. Magnesium StearateUSP/EP/JP Lubricant 0.5 1Ø
(Non-Bovine)
10. Stearic Acid USP/EP Lubricant 0.5 2Ø
Table 3: Excipients for Fax-Wax Matrix System
Item Compendia)
Excipient Function
# Status Low High
1. Cetyl Alcohol USP Erodable Retardant15.025.0
2. Cetearyl Alcohol USN Erodable Retardant15.025.0
~
3. Lactose (Fast USP/EP/JP Filler/Diluent 20.060.0
Flo)
4. Microcrystalline USPIEP/JP Filler/Diluent 16.730.0
Cellulose
(Avicel)
5. Calcium PhosphateUSP-NF Filler/Diluent 16.733.3
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Dibasic (Emcompress)
6. Colloidal SiliconUSPIEP/JP Glidant 0.5 2.0
Dioxide
7. Magnesium StearateUSPIEP/JP Lubricant 0.5 L0
(Non-Bovine)
8. Stearic Acid , USP/EP ~ Lubricant I 0.5 2.0
~ I
Table 4: Excipients for Hydrophilic/Hydrophobic Matrix System
Item Compendia) !o
Excipient Function
# Status Low High
1' Ethyl Cellulose USP-NF Hydrophobic polymer20.040.00
(Ethocel)
2' Eudragit RSPO USP-NF Hydrophobic polymer20Ø40.00
3' Eudragit S-100 USP-NF Hydrophobic polymer20.040.00
4' Kollidon SR USP-NF Hydrophobic polymer20.040.00
Methocel E4M Premium
. USP Hydrophobic polymer10.040.0
(CR Grade)
6 Methocel K4M (CR
. USP Hydrophilic polymer10.040.0
Grade)
7 ~Ydrophilic
' Pol in I rrolidoneUSP 5,0 10.0
Yv Y pY
Polymer/Binder
$' Lactose (Fast USP/EPIJP Filler/Difuent 20.060.0
Flo)
g Microcrystalline
Cellulose
, USP/EP/JP Filler/Diluent 16.730.0
(Avicel)
Calcium Phosphate
. USP-NF Filler/Diluent 16.733.3
Dibasic (Emcompress)
11. Colioidal SiliconUSP/EP/JP Glidant 0.5 2.0
Dioxide
12 Magnesium Stearate
. USP/EP/JP Lubricant . 0.5 1.0
(Non-Bovine)
13. Stearic Acid USP/EP Lubricant 0.5 2.0
Table 5: Excipients for Film-Coated Particulate System
I
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Item Compendia) ,
Excipient Function
Status Low High
1. Lactose (Fast USP/EP/JP Filler/Diluent 20.0 60.0
Flo)
2. Microcrystalline USP/EP/JP Filler/Diluent 16.7 30.0
Cellulose
(Avicel)
3. Calcium PhosphateUSP-NF Filler/Diluent 16.7 33.3
Dibasic (Emcompress)
4. Starch 1500 (Pre-USP-NF Glidant/Disintegrant5.0 10.0
gelatinized Starch)
5. Polyvinyl pyrrolidoneUSP Binder 5.0 10.0
K-
29-32
6. Sodium Starch USP-NF Disintegrant 1.17 3.3
Glycolate
(Explotab)
7. SodiumCrosscarmelloseUSP-NF Disintegrant 1.7 5.0
(Ac-Di-Sol)
8. Colloidal SiliconUSP/EP/JP Glidant 0.5 2.0
Dioxide
9. Magnesium StearateUSP/EP/JP Lubricant 0.5 1.0
(Non-Bovine)
10. Stearic Acid USP/EP Lubricant 0.5 2.0
11. Plasticized ethylcelluloseVendor's Coating system TBD TBD
dispersion specification
12. Plasticized methacrylateVendor's Coating system TBD TBD
dispersion specification
13. Plasticized polyvinylVendor's Coating system TBD TBD
acetate phthalatespecification
dispersion
CR formulations of the drug 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
ar
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 arid compression), and film-coating of
particulates (dry
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blend, wet granulation, kneading, extrusion, spheronization, drying, film-
coating, followed by
blending of differing; species of film-coated spheres, and compression).
[0283] In one version, a 100 mg CR formulation containing fillers, a glidant,
lubricants and a
hydrophilic polymer is made by direct compression. 1n this formulation, 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. 1
g) of this
blend is then mixed with Magnesium Stearate and Stearic Acid in a PE bag,
transferred 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. This formulation is described in the table below.
Table 6: 100 mg CR Tablet Formulation
Ingredient mgltab % wlw Wt.(g)
1. Ion channel modulating100.00 33.33 5.00
com ound
2. Starch 1500 15.00 . 5.00 0.75
3. Proso1v SMGG90 45.70 15.23 2.29
4. Lactase Fast Flo 91.30 30.43 4.57
5. Methocel K4M 45.00 15.00 2.25
6. Stearic Acid 1.50 0.50 0.08
7. Magnesium stearate 1.50 0.50 0.08
Total Weight 300.00 100.00 155.00
[0284] 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.
Table 7: Proposed Initial Compositions for CR Matrix Tablets
Item Formula hydrophilichydrophobichot melt
No. Ingredients % w/w %w/w %w/w
Ion Channel [ 33.33 44.44 44.44
Modulating ' I
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Compound
2. Methocel K4MCR)15.00- -
3. Cetyl Alcohol - - 22.22
4. Ethylcellulose - 8.80 -
5. Kollidon SR - 31.11
6. Starch 1500 5.00 - -
t
7. Prosolv SMCC90 15.23 - 15.56
8. Lactose 30.43 14.22 16.44
9. Stearic Acid 0.50 0.67 0.67
10. Magnesium Stearate0.50 0.67 0.67
(Non-Bov)
Total 100.00 100.00 100.00
* Tablet weight: 300 mg ** Tablet weight: 225 mg
b. IR tablets of (1R,2R)-2-C(3R)-HydYOxypyrrolidznylJ-1-(3,4-
dimethoxyphenethoxy)
cyclohexane fsionohyd~-ochloride (CaaFI3jNO4.HCl)
[0285] 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 IR tabletting are listed in the following table.
Outlined are the chemical
and brand names, compendia) status, function, and range of use levels:
Table 8: Excipients for IR Prototype Formulations
Item~cip;ent Compendia) Function
Status
# Low High
1. Sodium Starch USP . Disintegrant 1.0 3.0
Giycolate
2. Pre-gelatinized USP Glidant/Disintegrant5.0 10.0
Starch
3. Silicified MicrocrystallineUSP Filler/Diluent20.0 40.0
Cellulose
4. Polyvinyl pyrrolidoneUSP Binder 5.0 10.0
5. Lactose (Fast USP/EPlJP FiIledDiluent 20.0 60.0
Flo)
6. Microcrystalline USP/EP/JP Filler/Diluent16.7 30.0
Cellulose '
(Avicel)
7. Calcium PhosphateUSP-NF Filler/Diluent16.7 33.3
Dibasic (Emcompress)
8. Colloidal SiliconUSP/EPIJP Glidant 0.5 2.0
Dioxide
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9. Magnesium stearateUSPIEP/JP Lubricant 0.5 1.0
(Non-Bovine)
10. Stearic Acid USP/EP Lubricant 0.5 2.0
[0286] 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.
[0287] In one version, a 100 mg IR. formulation containing basic JR
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 dxug
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 Explotab and mixed for 2 minutes. A portion (e.g. 1 g) of this
blend is then
mixed with Magnesium Stearate and Stearic Acid in a PE bag, transferred back
to the bulk
blend via a #30 mesh screen and blended for 1 minute. Tablets are compressed
with a
suitable punch (e.g., a 9 mart punch) on a single punch press to obtain a
tablet hardness of 7-
12 KN. The formulation is described in the table below.
Table 9: 100 mg IR Tablet Formulation
ingredient mg/tab % w/w Wt.(g)
-
1. Drug (C20H31N04.HGI)' 100.00 33.33 5.00
2. Starch 1500 15.00 5.00 0.75
3. Prosolv SMCC90 60.00 20.00 3.00
4. Lactose Fast Flo 117.00 39.17 5.88
5. Sodium Starch Glycoiate3.00 1.00 0.15
(Expiotab)
6. Stearic Acid 3.00 1.00 0.15
7. Magnesium Stearate1.50 0.50 0.08
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Total Weight 800.00 100.00 ~15.00~
c. In-vitro Dissolution of IR arad CR Tablets
[0288] 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). For
example, a
weighed tablet of the drug (e.g. (1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy) cyclohexane monohydrochloride) is added to a measured
volume of a
solution containing 0.9% NaCI irl water, where the solution volume will be
such that the
active agent concentration after release is less than 20% of saturation. The
mixture is
maintained at 37°C and stirred or shaken slowly to maintain the tablet
in suspension. The
release of the dissolved drug as a function of time may then be followed by
various methods
known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, and
the like,
until the solution eoncentration becomes constant or until greater than 90% of
the active agent
has been released.
[0289] In one variation, various IR. and CR tabletted formulations of (1R,2R)-
2-[(3R)-
Hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride
(described below) 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 IR formulation of the ion
channel modulating
compound. This IR formulation is described in Table 10, Part I below. More
than 80% of the
drug in the IR form has dissolved by fifteen minutes.
[0290] Release profiles for different CR formulations show that the CR
formulations dissolve
in hours rather than minutes (Figure 3). Figure 3 shows a comparison of four
different
hydrophilic CR tablets, a hydrophilic non-cellulose tablet, a hot-melt wax
tablet, and two
hydrophobic tablets. The formulations of these CR forms are given in Table 10,
Part I and
Table 10, Part II.
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Table 10 Part I: IR and Hydrophilic CR tablet formulations
IR tablet
Tablet Type: HydrophilicHydrophilicHydrophilicHydrophilic
formulation
CR tabletCR tabletCR tabletCR tablet
1 2 3 4
ingredientltablet strength:100 100 mg 100 100 300
mg/tablet % mg mg mg mg
Ion Channel Modulating 100.00 100.00 100.00 100.00 100.00
Drug (C20H31N04.HCI)
Starch pregelatinized 95.00 15.00 10.00 10.00 10.00
1500
Silicified Microcrystalline
Cellulose -Prosolv 60.00 45.70 32.00 32.00 32.00
SMCC90
lactose Fast Flo 117.50 91.30 40.00 40.00 40.00
Sodium Starch Glycolate-Explotab3.00
Hydroxypropyl Methyicellufose 45.00 40.00 40.00 40.00
Methocel K4M
Cetostearyl Alcohol
- KaIco16850
Polyethylene Glycol
8000
Koliidon SR
Ethyl Cellulose. Standard
4
Eudragit RSPO
Anhydrous Emcompress
Stearic Acid 3.00 1.50 1.50 1.50 1.50
Magnesium Stearate-Non-Bovine1.50 1.50 1.50 1.50 1.50
Total Weight: (mg) 300.00 300.00 225.00 225.00 675.00
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Table 10 part II: GR Formulations
Hydrophilic
Wax Hot-MeltHydrophobicHydrophobic
Tablet Type: CR
MatrixWax CR TabletCR Tablet
non-cellulose 1 2
CRTabietCRTablet
tablet
ingredientitablet strength:100 mg 100 100mg 100 mg 100 mg
mgltabiet- % mg
Ion Channel Modulating 100.00 100.00100.00 100.00 100.00
Drug (C20H31N04.HCi)
Starch pregelatinized
1500 33.75 50.00 35.00
Silicified Microcrystalline
Cellulose -Prosolv
SMCC90
Lactose Fast Flo 37.00 37.00 32.00
Sodium Starch Glycofate
-Explotab
Hydroxypropyl Methylceilufose-
Methocel K4M'
Cetostearyl Alcohol 35.00 50.00
- Ka1co16850
Polyethylene Glycol 45.00
8000
Kollidon SR 70.00 45.00
Ethyl Cellulose Standard 20.00
4
Eudragit RSPO 15.75 45.00
Anhydrous Emcompress 27.50 32.00
Stearic Acid 1.50 1.50 1.50 1.50 1.50
Magnesium Stearate-Non-Bovine1.50 1.50 1.50 1.50 1.50
Total Weight: (mg) 225.00 225.00225.00 225.00 225.OD
Combinations of ion channel modulating coni~ounds and biomedical devices
j0291] 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.
j0292] 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
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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).
[0293] Implantable systems incorporating 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.
[0294] Biomedical devices appropriate for use in conjunction with the ion
channel
modulating compounds described here could be used to treat or prevent
cardiovascular
disorders. For example, formulations of the ion channel modulating compounds
could be
used in combination or conjunction with angioplastic balloons, cardiac
monitors, stems
(including drug eluting stems), defibrillators, 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.
[0295] 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. In 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.
EXAMPLES
[0296] The following examples demonstrate the methods described in this
application. These
examples are not intended to limit the scope of the described methods and
formulations and
are included for illustrative purposes.
Example 1 - Termination ~ atrial~brillatiofz - Step dosing study in human
sub 'ects
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[0297] A prospective double-blind, placebo-controlled, randomized, dose-
response trial was
conducted. The compound used in these studies is (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-
(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride, which has structural
formula
O ,~ OCH3
~~~'~n,~N
."~~W lOH OCH3
.HC1
[0298] To be eligible, patients had to have a rhythm of sustained atrial
fibrillation with a
duration of 3-72 hours at the time of randomization. Patients were managed in
accordance
with ACC/AHA/ESC anticoagulation pracrice guidelines. Patients > 21 years of
age were
eligible. AlI patients had to be hemodynamically stable (systolic blood
pressure of 90-160
mm Hg with diastolic blood pressure <95 mm Hg).
[0299] 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 uncorrected
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 (<SO 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-White syndrome; COPI? requiring daily-bronchodilation therapy;
cyanotic or other
significant congenital heart disease; concurrent treatment with known QT
prolonging drugs or
class I or III anti-arrhythmic agents (unless the medication was discontinued
more than five
half lives before enrollment); oral amiodarone in the prior 6 months or
intravenous
amiodarone in the prior month; or end stage diseases. No alcohol, caffeine,
herbal remedies
or smoking were permitted during the study. Pre-enrollment treatment with 13-
adrenergic
blocking agents, calcium antagonists, and digoxin for control of ventricular
rate were
permitted.
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[0300] Eligible patients were approached and provided informed written
consent. To enter
the trial, all patients had to demonstrate normal serum electrolytes (serum
potassium not < 3.5
mEq/L, magnesium not < 1.5 mEq/L), serum creatinine of 1.8 mg/dL or greater,
hemoglobin
not < 9 g/dL in women or < 11 g/dL in man, and liver enzymes less than l .5x
maximal
normal values.
[0301] Patients were randomized to one of three groups and in each group
received up to two
10-minute intravenous infusions, separated by 30 minutes. Infusions were
placebo followed
by placebo, 0.5 mg/kg followed by 1.0 mglkg of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl)-1-
(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride, or 2.0 mg followed by
3.0 mg
(1R, 2R)-2-[(3R)-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride (follow-on dose, efficacy dependent). Doses for patients
weighing >113
kg were capped as if the patient weight was 113 kg. If the arrhythmia did not
terminate or
persisted 30 minutes after the end of the fixst infusion, the second infusion
was administered.
Outcomes: Efficacy outcomes were adjudicated by the steering committee (DR,
BHR, AME)
prior to unblinding of treatment allocation; disagreements were resolved
following second
review and consensus. The primary efficacy end point of this study was the
termination of
atrial fibrillation. Success was defined as termination for any length of time
during infusion or
30 minutes after initiation of infusion. Secondary endpoints included: number
of patients in
normal sinus rhythm (NSR) at 0.5, 1 and 24 hours after last infusion, as well
as the time to
conversion.
[0302] A Holter rhythm strip continuously monitored ECG, vital signs (blood
pressure and
heart rate) and Q2 saturation were recorded every 2 minutes from the start of
infusion to 5
minutes after, as well as at 15, 30, 60, 120, 240, 360, and 480 minutes and at
discharge and 1-
week fallow-up. 12-lead EGGS were obtained befoxe dosing and every minute
during infusion
to 5 minutes after, as well as at 15, 30, 60, 120, 240, 360, and 480 minutes
and at discharge,
24 hours and 1-week follow-up, and at the time of arrhythmia termination ox
significant
rhythm changes. ECGs were interpreted by individual investigators and
independently
verified by a core lab cardiologist blinded to study treatment. Venous blood
samples were
drawn for (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(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
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if the arrhythmia 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 occurred that in the
investigator's opinion
was a threat to patient safety, a new bundle-branch block developed, QRS
increased >50%,
uncorrected 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 use of other antiarrhythmic agents was
discouraged until 12
hours after the (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-I-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride infusion, unless the
investigator
considered it necessary to restore sinus rhythm earliex.
(0303] The sample size was based on estimates of a placebo conversion rate of
35%, (IR,
2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(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.
(0304] All patients who received study medication were included in the safety
analysis, and
55 patients were evaluated for efficacy. Data are presented as mean ~ SD,
median with
interquartile range (IQR), all tests were performed as two sided and 95% CI
were produced; p
< 0.05 was considered statistically significant unless stated otherwise.
Analysis of the
relationship between termination of atrial fibrillation and treatment was
performed using a
chi-square analysis. In cases of small cell frequencies, the Fisher's exact
test was used. A
Cochran-Armitage test statistic with table scores was used to test the
ascending dose
evaluation of efficacy.
[0305] Patients who were electrically cardioverted were not evaluated for
secondary
endpoints. The time to conversion from the start of the first infusion was
analyzed by the Cox
regression method of event time analysis and one-way ANOVA. Assessment of the
significance of time point values and mean change from baseline to each follow-
up reading of
ECG intervals (QRS, QT, QTc), blood.pressures, and heart rates were made
within dose
groups using paired t tests, and comparisons among dose groups were made using
a one-way
ANOVA.
[0306] Fifty-six patients with recent onset (new or recurrent) atrial
fibrillation were
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administered blinded treatment Of the 9 patients randomized but not treated, 6
spontaneously
converted to NSR and did not receive drug, 1 patient converted to atrial
flutter, 1 patient
withdrew consent and 1 was a screening error. The treatment allocation was as
follows:
placebolplacebo, 20; 0.5 mg/kg + 1.0 mg/kg (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride, 18; and 2.0 mglkg + 3.0 mg
(1R,
2R)-2-[(3 R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride, 18.
(0307] The mean age of the patients was 61 years (range 24-88 years), 61% were
male. The
average duration of the arrhythmia was 17,813 hours in the placebo group,
23.622 hours
and 24.720 hours in the RSD-1 and RSD-2 dosing groups, respectively. Overall,
62% of
patients had at least one previous episode of atrial fibrillation. Baseline
clinical characteristics
were similar across groups except that patients in the placebo group tended to
moxe frequently
report atrial fibrillation in the past than in the (1R, 2R)-2-[(3R)-
hydraxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride dosed groups.
[0308] 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 occurred 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.
[0309] The most common AEs experienced in this study were cardiac disorders,
reported by
7 patients (35.0%) in the Placebo group, 4 patients (22.2%) in the RSD-1
group, and 3
patients (16.7%) in the RSD-2 group. In addition to the serious adverse events
discussed
below, the 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. Other common AEs occurnng with a similar frequency among treatment
groups were
nervous system disorders, general disorders, investigations, and infections
and infestations.
(0310] 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
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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.
[0311] A transient cerebral ischemic attack occurred 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 recurrent
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.
(0312] The cumulative atrial fibrillation termination within 30 minutes of
infusion was
61.1% (11 of 18 patients) after 2 + 3 mg/kg (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride infusion (the "RSO-2"
group), 11.1
(2 of 18 patients) after 0.5 + 1 mg/kg (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-
(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride (the "RSD-1 group") and 5.3%
(1 of
19 patients) after placebo + placebo. Paired comparisons indicated a
statistically significant
difference (p = 0.0003; Figure 4) between placebo (5.3%) and the RSD-2 group
(61.1%).
There was no significant difference (p = 0.51) in the success rates between
the RSD-1 group
and placebo. Of the 11 successful terminations in the RSD-2 group; u8
terminated on the first
infusion (44.4% or 8/11 = 73%).
[0313] The number of patients in NSR at 30 minutes post infusion was 56% (10
of 18
patients, p=0.0008) in the RSD-2 group, compared to 11% (2 of 18 patients) in
the RSD-1
group (p = 0.51) and 5% (1 of 19 patients) in the placebo group. The number of
efficacy
evaluable patients iri NSR at 1 hour post infusion was 53% (9 of 17 patients,
p = 0.0014) in
the RSD-2 group, and 11% (2 of 18 patients, p = 0.51) in the RSD-1 group,
compared to 5%
(1 of 19 patients) in the placebo group. Patients in NSR (excluding those
electrically
cardioverted) at 24 hours post infusion was 79% (11 of 14 patients, p = 0.14)
in the RSD-2
group, and 56% (5 of 9 patients, p=0.80) in the RSD-1 group compared to 50% (5
of 10
patients) in the placebo group.
[0314] The median time to conversion to NSR from the start of the first
infusion in the 11
responders in the RSD-2 group was 14 minutes (range, 3 to 871 minutes; p =
0.016)
compared to the 5 spontaneous responders in the placebo group with a median
time of 162
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minutes (range, 58 to 1119 minutes). The median time to conversion to NSR from
the start of
the first infusion in the 5 eventual responders in the RSD-1 group was 166
minutes (range, 1
to 332 minutes; p = 0.886 vs. placebo).
[0315] 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.
[0316] Within the study period (24 hours) electrical cardioversion was
attempted in 9 of 19
(47%) placebo treated, 9 of 18 (50%) RSD-1 treated and 4 of 18 (22%) RSD-2
treated
patients and was successful in 8 (89%), 9 (100%) and 4 (100%) patients,
respectively.
[0317] Mean peak (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride plasma levels were 5.8
,ug/mL (range:
4.0 to 8.6 pg/mL) in the patients that received both the 2.0 and 3.0 mg/kg
infusions of (1R,
2R)-2-[(3R)-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride and 1.9 ~g/mL (range: 0.1 to 3.4 p,glmL) in those that
received both 0.5
and 1.0 mg/kg (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl)-1-(3,4-
dirnethoxyphenethoxy)cyclohexane monohydrochloride. (Figure 5) Maximum plasma
levels
were seen at the end of the second infusion. Plasma drug levels at 24 hours
post infusion were
below the limit of quantitation (5 ng/ml) in the majority ofpatients who
received RSD-1.
Similarly, negligible plasma levels were seen at 24 hours in the RSD-2 group;
mean plasma
levels wexe 0.017 ~,g/rnL (range: <0.005 to 0.028 ~Cg/mL).
[0318] In those patients that responded to (atrial fibrillation converted) and
received only the
2 mg/kg infusion, mean peak plasma levels at the end of infusion were 2.6
pg/mL (range: 1.4
to 4.5 pg/mL). The median plasma level at the time of atrial fibrillation
conversion in these
patients was 1.3 ~,g/mL (range: 1.1 to 3.S.~g/mL). The mean terminal
elimination half life in
these patients was 3.1 hours (range: 1.7 - 5.4 hours).
[0319] This dose-finding study demonstrated that the upper dose of (1R, 2R)-2-
[(3R)-
hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
(2+3
mglkg) rapidly and effectively terminated atrial fibrillation compared to
lower dose (1R, 2R)-
2-[(3R)-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride
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and placebo. (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)
cyclohexane monohydrochloride rapidly converted atrial fibrillation patients,
often during the
infusion phase. There were no serious adverse events associated with (1 R, 2R)-
2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
at
plasma levels up to 8.6 ,ug/m1, and observed SAEs were more common in the
placebo group.
In contrast to other antiarrhythmic drugs used for conversion of acute atrial
fibrillation, there
were no instances of drug related pro-arrhythmia. While these initial findings
will require
confirmation in larger scale clinical trials, this safety profile coupled with
an efficacious and
rapid onset confirms that (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride is a promising new agent for
the
medical conversion of acute atrial fibrillation.
Example 2 -Pharmacokinetic evaluation o f oral dosin~in hufnan subiects.
[0320) This prospective, randomized, placebo-controlled, double-blind,
ascending dose study
was conducted to assess safety and oral absorption of (1R; 2R)-2-[(3R)-
hydroxypyrrolidinyl]-
1-(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. The
pharmacokinetics was assessed through measurement of.(1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
levels in
both urine algid plasma.
[0321) The Cm~ in fasted volunteers was 1.8 ~ 0.4 ~Cg/ml after the 5 mglkg
p.o. dose and 1.9
~ 0.5 ~.g/ml after the 7.5 mg/kg p.o. dose. In fed volunteers, the C",a,~ was
1.3 ~ 0.7 ,ug/ml
after the 5 mg/kg p.o. dose. There were no statistically significant
differences in C",~, time to
maximum plasma levels (TmaX), or bioavailability (F%) between the groups. 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 mglkg fasted
respectively, indicating
that (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane
monohydrochloride is rapidly and extensively absorbed after oral
administration. The plasma
levels achieved were well within the therapeutic range (median plasma level at
EDso =1.3
~.g/ml) as observed in the recently completed intravenous trial.
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[0322] (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl~-1-(3,4-
dimethoxyphenethoxy)cyclohexane
monohydrochloride was found to be well-tolerated in oral doses of up to 7.5
mg/kg. Vital
signs, BP and lab results remained normal in all subjects. There were no
changes in QT or
any ECG intervals observed in any of the dosing groups.
[0323] This study was a prospective, randomized, placebo-controlled, double-
blind,
ascending dose bioavailability study of an orally administered aqueous
formulation of (1R,
2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(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.
[0324] This study was conducted to determine the oral absorption and
bioavailability of (1 R,
2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
rnonohydrochloride (relative to intravenous administration in a previous
study, MDS Pharma
Services, Project 26450, August 2001) in normal healthy human volunteers. The
study was
also conducted to determine the safety and tolerability of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
given as
a single oral dose of 5.0 or 7.5 mg/kg in fasted and fed .(5.0 mg/kg only)
normal healthy
human volunteers.
[0325] The study was a prospective, randomized, placebo-controlled, double-
blind ascending
single-dose dose assessment of the oral bioavailability of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(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. After completion of each dosing block and
assessment of
clinically significant findings, the blind was broken and (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
plasma
levels were analyzed prior to continuation of the next dosing block. Interim
safety review
meetings were held to review all of the available data after dosing blocks 1
and 2.
[0326] All subjects were admitted to the study facility the evening before
dosing and were
monitored for 24 Hours in the facility post-dose with a 1-week +/- 3 days
follow-up visit.
Volunteers received a single dose (150 ml solution) of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl~-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
or
placebo given on one occasion. The first 8 subjects were randomized to receive
either placebo
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(n=2) or to receive a single oral administration of 5.0 mg/kg oral dose (n=6).
The first 8
subjects were fasted from midnight prior to dosing until four hours post-dose.
The second
group of subjects were assessed at the same dose (5 mglkg) with fed subjects
(n=6) and
placebo (n=2). A standard breakfast was administered concomitant with dosing.
The third
group of 8 subjects were randomized to receive either placebo, (n=2) or to
receive a single oral
administration of 7.5 mg/kg (n=6). These subjects were fasted from midnight
prior to dosing
until four hours post-dose.
[0327] The subjects for this study were normal, healthy males and females as
defined by the
inclusion and exclusion criteria described below:
Inclusion Criteria
a) 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 (IUD), condoms in combination with a spermicidal cream,
total abstinence or sterilization. Males will be advised to refrain from
unprotected
_:~: sexual intercourse (i.e., without adequate contraceptive method) until
three months
after the follow-up screening).
b) No clinically important abnormal physical findings at the screening
examination.
c) Normal ECG.
d) Body weight between 45 to 95 kg and a body mass index of 18-27 kg/m2.
e) Able to communicate well with the investigator and to comply with the
requirements of the entire study.
f) Provision of written informed consent to participate as shown by a
signature on
the volunteer consent form.
Exclusion CriteYia
a) 90 mrnHg > systolic blood pressure > 160 mmHg, or, 65 mm Hg > diastolic
pressure
> 95 mrnHg. These will be measured 3 times after sitting for 3 minutes and
averaged
to determine a baseline BP.
b) 50 bpm >_pulse rate ~0 bpm.
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c) PR > 0.21 sec, QRS > 0.11 sec, QT~B > 0. 430 sec fox men and QT~B > 0.450
sec for
women.
d) Participation in any other investigational drug study within 60 days
preceding the
start of the study, or participation in more than 3 other drug studies (for
men) l more
than 2 other drug studies (for women) in the past 10 months.
e) Administration of prescription or over-the-counter medication during the
period 0 to
days before entry to the study including aspirin. (Exceptions to this
criterion
include the use of hormone replacement therapy or oral contraceptives by
female
subjects.)
f) Administration of antacids, gastric reflex, anti-ulcer or gastrointestinal
pro-kinetic
medications in the period of 0 to 30 days before entry to the study unless
agreed upon
by Sponsor and Investigator.
g) Existence of any surgical or medical condition which, in the judgment of
the clinical
investigator, might interfere with the absorption, distribution, metabolism or
excretion of the drug.
h) Donation of blood within 60 days preceding the start of the study, or,
donation of
more than 1.5 liters of blood (for men) / more than 1.0 liters of blood (for
women) in
the past..l0 months. (The exception to this criterion is, blood sampling for
screening,
admission and baseline tests for this study is permitted.)
i) Loss of greater than 250 rnl of blood within 60 days preceding the start of
the study.
j) Known serious adverse reaction or hypersensitivity to any drug.
k) Inability to communicate or co-operate with the investigator because of a
language
problem, poor mental development or impaired cerebral function.
1) Positive drug screen, positive Ab to HIV, HCV, and positive Ag to HBV
m) History of drug or alcohol abuse.
n) Abnormal screening test results (clinical chemistry, hematology or
urinalysis).
o) Family history of QT abnormalities or congenital QT syndrome.
p) Any herbal or alternate medicines during the period 0 to 5 days before
entry to the
study.
q) Frequent use of antacids
r) History of gastro-intestinal or cardiovascular problems.
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s) Any other condition that, in the opinion of the clinical investigator,
would make it
unwise to enter the subject into the study.
[032] No alcohol, caffeine or smoking were permitted from admission to the
study facility to
discharge. No herbal remedies, medicines or alternative medicines were
permitted from
admission to the study facility to discharge with the exception of
aspirin/paracetamol which
was permitted from 4 h post-dose onwards.
[0329] 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.
[0330] 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 subj ect enrolled in the study was characterized for cytochrome
P450 2D6
expression by genotyping using a blood sample.
[0331] The study 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, l, 2, 4, 6, 8, and 24 hours after druglplacebo
administration; at
follow-up visit; and in the event of an SAE (none occurred). 12-lead ECGs were
recorded at
the following timepoints: screening; admission; pre-dose; immediately
following dosing;
0.25, 0.5, l, 2, 4, 6, 8, and 24 hours after drug/placebo administration; at
follow-up visit; and
in the event of an SAE (none occurred). 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
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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 tirnepoints
via venipuncture or sampling cannula into lithium heparin tubes: 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
occurred). Pharmacokinetic (PK) parameters for each subject were calculated
usi g
WinNonlin (Pharsight Corp., Palo Alto, California, USA). A non-comparhnental
model was
used to calculate parameter estimates. The oral bioavailability of (1R, 2R)-2-
[(3R)-
hydroxypyrrolidinyl)-1-(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 study (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. Clinical chemistry,
hematology,
and urinalysis at screening, admission, at 1 hour post-dose and at discharge.
Holter
monitoring continued for up to 24 hours post-dose. Holter monitors were read
at a central
reading centre. The nature of any adverse event, its time of onset, its
duration and severity,
action taken, if any, and the investigator's opinion as to whether it was
related to the test drug
was recorded on the AE Form. Duration of the follow up of an adverse event was
until
recovery from the event,was evident, or until the event was judged medically
stable or
permanent. Subjects were monitored in the study facility until all adverse
events resolved.
[0332] The study drug showed rapid and extensive absorption after a single
oral dose in both
fasted and fed subjects (Table 11 and Figure 6). The majority of subjects
achieved maximal
plasma levels (C",~) within 30-60 minutes of dosing. The Cm~X in fasted
subjects was 1.8 ~
0.4 pg/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 Cm~ in fasted subjects was 1.9 ~ 0.5 ~g/ml after the 7.~ mg/kg
p.o. dose:
There were no statistically significant differences in Cm~, time to maximum
plasma levels
(TmaX), or bioavailability (F%) between the groups. One subject with slow
clearance and a
bioavailability of approximately 240% (#OS) was excluded from the
bioavailability
calculations.
Table 11. PK and Bioavailability Results
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5 mg/kg 5 mg/kg 7.5 mg/kg
fasted fed fasted
Cmax (,ug/ml)1.80.4 1.30.7 1.90.5
Tmax (min) 5535 7041 4516
AUCaII 470330 330250 29070
AUCinf 490350 340240 30080
AUCldose 9871 6749 5719
F% 71~21* 6950 5819
(min-max) (46-105)* (15-i39) (33-89)
* excluding one outlier (F=240%)
[0333] 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 mlkg fed and 7.5 mg/kg
fasted
respectively, indicating that (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl)-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride is rapidly and extensively
absorbed
after oral administration. The plasma levels achieved were well within the
therapeutic range
(median plasma level at EDSO = 1.3 ~.g/ml) as observed in the recently
completed intravenous
studies.
[0334] The study drug was well tolerated at oral doses of 5 - 7.5 mg/kg in
normal healthy
volunteers. Vital signs, BP and lab results remained normal in all subjects.
Almost all of the
adverse events observed were considered not related to drug and all except one
of the
observations were mild in nature. Single observations of loose stools, bitter
taste and a visual
disturbance were considered possibly related to drug. A further volunteer
reported two
episodes of transient paraesthesia of the right hand that was also considered
possibly related
to drug. There were no significant changes in clinical laboratory tests or
vital signs. There
were no clinically relevant changes observed in QTcB, QT, JT, PR, QRS, or HR
intervals and
no clinically significant findings found in the Holter recordings.
Example 3 - Plaa3~macokinetic evaluation of (IR, 2R)-2-(f3R)-h
d~oxypyrrolidinylJ-1-
(3,4-dimethoxyplzenethoxy~cyclohexatze nzotzohydroclzloride in dogs.
[0335] In this study, the pharmacokinetics of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride in beagle dogs after dosing
via oral
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gavage, intraduodenally (IT7) and intracolonically (IC) was investigated.
Pharmacokinetic
parameters such as AUC o.t, CmaX and T",~ were determined. The segmental
dependence to
absorption of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride was also evaluated.
[0336] Dosing solutions for all routes of administration were prepared using
the same
procedure as follows: 425 mg of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride (lot#BC-145-39, 99.3%
active) was
weighed into a precleaned 20 mL glass vial. 21 mLs of water was added and the
sample was
inverted several times to dissolve all powder. At the time of dosing all
solutions were clear.
[0337] The pharmacokinetics of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride was evaluated in male beagle
dogs
ranging in age from 1 to 2 years. All animals were housed one per cage. The
animals were
fasted for a minimum of 12 hours prior to dosing. Food was returned to the
animals at four
hours post-dose. Water was withheld fox one hour predose and supplied ad
libitum at one
hour postdose. The same six beagle dogs (crossover design) were used for each
dosing leg of
the study. All animals were dosed on the same day via the same route of
administration.
The numbers of the animals and the dosing regimen are presented in Table 12.
Table 12
Study 7?esign
-~~.,, -.-
. ~. ; ~ . r
° ~ . - $ ~__~
,:. . ~ : . _ ~ .~ ,~ ~_,
"~, im, ..r3. . 5. ~ u,z.., _ X., ,a -..~'.
~d 2.;i.c~:..: .:=7, . .~,~~:...~.... .,...I.'-..:~.h.,Er.~.., i.. ~.. _r.;
.~_ (......r..J....
'~... 'a'». .. ,: f~ .': - ;.2 W?fA -. ~ ..,n. r - -,.x .~ . ..~ M'..
y~ ;l 2' E . ~-~-, k h, a.r~ ~a.- :u
.~a ~~s .,.45 ~ v'~ », 2 ~'. 'F:' ': ::~ ;'oh... "aJ.~" 1. ,s y xt,... - ~':,
'
-. ..~t _ .;u,.y - .,._h"' 3... .,s'3...).,. .~~L...~n .,.'~e~c. ,~-..;'r -
d..~.;:
..~ ,s . .~ a '~. :~ ~~'. ~, ><. .w. P~.;.y;..- -~'..,.~, ~...."~"~ a ,a;_."
:."~'~.,".. r
F-x ,; 2z~ .. ~ .- e-. .~,- ;''ass. ~ z,_.. ,~.t", .,:, r-, ca~-," ~, ~$:>,se"-
-rf ' r ti.,.x-. !:$.~,.;, ,;~. ,~ ,i- . r ~_,~ x _~....,~ ~, yr~.u ~,t~.
..sk'.~::-~- , ."t . y-,.,- .hc : a, n,
.~~~q--<i. >h.:t; aFV.a..rxds-.~'fs.< ~,..;,~,.,x-,.~ .SS , . n:,.F. .. .k:~-~
arli ....kW_,s,. -;
- r 's.~~>," . ~~~ ~ r : n '. ~% ,~. z-," p't5ar ~ ~Y., x~"~~', . _ . ''r;.~c~
~ .., ..~_:w ~ ~ r ~.~ L' ~';~'.. ~~v~az'3"~~ ~' .
R~~~'~'.~~,'.e- -t ~~~ p-'..>' ', .. ~M';~ ~ a,~':,. -_, '~.">!, rbEP - ~ ,.
.,d'- >, ~~ y ~. .~,.'~.''d'"'a~. ,x .,.,., , : xt "
w ~,,'* ~~ar.
~~ .."r'%3~ =rs,r~ ,"o- ~"-~~ .,~" - .2v 7. .-'~-..,-a,"" , :'. ''' , J, ' '.N
~ ~ , r ,.~~, ~".. .-,, _ ~ , x. Q a : >~
x F ~ ~~~ r ~. ~'.'
.~~ s .. _ ~, q,;'> .. s~..,_.
Y 7 >r
!y_: F 3Hc-f ,4 rr -.~~ "''s'~ F~~~,, ; 1, F .~ ~-~~~~ si ~ z'Y~ - .
. a -. a ,Y~~
- .adz , ~.d . -.k'3 s~?aa ~ ~_z
v
,YM F~' Jv-d!-
W.. it ~ -..-,...,.~_&ire n , ~ z ~r~ , , . ~ ;, ø-at ; '&z,-. r~ .~ _ , ~, _
, Y . . .~'::r;' ,
. ~-'a~~..e"~.~,.F~l . a '; ~;.~", .; . ~ r . ,. j - , <,-.Y; : ~;~ . ,, c .,
M , ~ G ~~' - ~' ~~A 'r "so., s~ ,
x.'s,...~ ::W~..._ >-~.a'~ ~,~.,_-~ ,'E~;~_.~~,-':~'~ ~. ~,,,~ -'- , n~".~-
~<<.r'r~
.v~ .~~ t~~'.:c...~~,.n" .~~".xx..~::,~'.,.a.>
..~.,~",~.~..r~,d<=..ri."~,x~....~6S.o-r"r~~.~,~-. ~k~..'~ ,,~,~'.x.
f,f..,y..~:~"i~.,= a ,.yY,~c~...a~,~Y.
~~. -." y...
Ol-(10213) 12.9 ORAL GAYAGE 0.25 5.0
18-(20352) 9.6 ORAL GAVAGE 0.25 5.0
I 37-(20741) 9.6 ORAL GAVAGE 0.25 5.0
40-(20941) 9.4 ORAL GAVAGE 0.25 5.0
44-(10102) 12.3 ORAL GAVAGE 0.25 5.0
45-(20191) 12.1 ORAL GAVAGE 0.25 5.0
Ol-(10213) 12.9 INTRADUODENAL 0.25 5.0
II 18-(20352) 9.4 INTRADUODENAL 0.25 5.0
37-(20741) 9.6 INTRADUODENAL 0.25 5.0
40-(20941) 9.5 INTRADUODENAL 0.25 5.0
127
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
44-(10102)12.4 INTRADUODENAL 0.25 5.0
45-(20191)11.8 INTRADUODENAL 0.25 5.0
01-(10213)13.1 INTRACOLONIC 0.25 5.0
18-(20352)9.6 INTRACOLONIC 0.25 S.0
III 37-(20741)9.7 INTRACOLONIC 0.25 5.0
40-(20941)9.7 INTRACOLONIC 0.25 5.0
44-(10102)12.8 INTRACOLONIC 0.25 5.0
.
45-(20191)12.2 INTRACOLONIC 0.25 5.0
[0338] Animals were dosed via a chronic intraduodenal or colonic access port
or by oral
gavage. Blood samples were taken from a foreleg vein via a butterfly catheter
at the
following time points: Oral gavage, ID and IC: 0 (pre-dose), 5, 15, 30, 60,
120, 240, 360, 480
and 1440 minutes postdose. The blood samples were withdrawn and placed into
tubes
containing sodium heparin as anticoagulant. Blood samples were then
centrifuged at 3,000
rpm for 15 minutes at 4°C.
[0339] (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane
monohydrochloride was extracted from the plasma via solid phase extraction
then analyzed
by LC/MS/MS. Pharmacokinetic analysis was performed on the plasma
concentration of (1R,
2R)-2-[(3R)-hydroxypyrrolidinylJ-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride for each individual dog at each time point. The data were
subjected to
non-compartmental analysis using the pharmacokinetic program WinNoxiLin v. 4.1
(1).
Pharmacokinetic parameters are given in Tables 13, 14, and 15.
Table 13
Phanmacokinetic Parameters of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride after Oral Gavage
Administration
S~ ~~ ~ .'~r~~M ~ ~~~~ ~~~ # t ';N,''N'
~ ~:~ ~ "- ~ ~i ~ s ~ -:.i y ~~~yv
a ~~ a ~' ~ ;x~
a~~~~r~ , _''r~b fix
;' ~ # a ; fi ~_ ~~s r 54
~ ~. s ~ "
T .~ ~ ~
~ ~
g
~ / sf'~~ ~B ~ ~ ~ fi
~._,,;; ~ G ~e.. 9 . ~'e~~ ~~NE ~'~~'"
7~ . ., ".;..~ '.
~~ ~; ~~
. ~
COMPOUND Ol 40165 332 30
18 14811 167 30
37 9568 92.6 30
40 78324 447 30
44 9883 76.8 60
45 6624 1 61.8 30
128
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
Average (SD,
265.63 196 35
28167 158 12
N=6)
Average* (SD,
16211 146 36
12263 100 12
N=5
Average of N=5, Dog 40 is removed from these averages
129
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
Table 14
Pharmacokinetic Parameters of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride after Intraduodenal
Administration
z~'a~ 1'~ u~ n ~i~"x.~i. ~ ~;r~ y "'
AG ~ ~ ~ ~"~~ ~ -~'* ~~~.r ,';~r)~,
-~ ,~~ : (i ~ ~
K ,
~
~
~
~~ .
_ ', ~ .. P pd~, ~~ ~~. V.. S.,'
_ 7 L~ f~ 1 ~'Y. , t v of c4 ~ ~~
~~~~ c 1 3 4t, .~~'::~f
a f'~ 3 N ~'>
' (
ex , ~, ~ ~
~ ur ~y~i~~v~ ~~~ ~~ ~
ky : atro s ~ ~'
' f
~
~
'~
~ z t ~ ,1~I~
: K_ 1_n , ~~1~TY1~..~,._
,~_ ,- . x r.~'-... ..: ~
.~.,~z. .
s, .r~ ...
'
,
~
O1 45301 286 30
18 30992 _ 343 15
37 13106 122 15
40 79131 639 30
COMPOUND44 14056 140 30
A 45 10960 130 15
Average (~-SD,
32257 277 23
26535 200 8.2
N=6)
Average* (SD,
22883 204 21
13296 g2 7.3
N=5)
*Average of N=5, Dog 40 is removed from these averages
Table 15
Pharmacokinetic Parameters of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride after Intracolonic
Administration
~ i ,A~~~:. y~~~ aX
{ ; x Ex ~
~ ~ ~n~n. ,' " ~~, '~,
.f ~L ~~1
., .
::;~
01 38891 158 60
18 21948 187 15
37 6923 39.1 15
40 88823 449 30
44 6495 35.1 30
45 5560 65.8 15
Average (SD, 2g107 156 28
N=6 32449 157 18
,
Average* (SD,15964 97 63 27
N=5) 12970 17.5
*Average of N=5, Dog 40 is removed from these averages
[0340) No adverse reactions were observed following oral gavage, intraduodenal
or
intracolonic administration of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride in beagle dogs.
[0341] The nominal concentration of the dosing solutions was 20 mg/mL. The
dosing
solutions were analyzed post-dosing and the concentrations were determined to
be 16.6, 17.0
and 17.5 mg/mL for the oral gavage, intraduodenal and intracolonic dosing
solutions,
130
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
respectively. These values were used in all calculations.
[0342] Average plasma concentrations (~ SD) of (1R, 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-
(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride for each point and
route of
administration are shown in Table 16.
Table 16
AVERAGE ~ SD (N=6) PLASMA CONCENTRATIONS (NG/ML) OF (1R~ 2R)-2-[(3R)-
hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane monohydrochloride
k. ',:: L,
: ' S;x
r~ _.. -~. ~v.
.,.".~. .. G -A'r
k~ ". » . as.~...y.. .,-i.".
$ry:.,f W
s-... l _
3. Sw. 3w --. i- ~:. . ~ ~ y~," '. :"Ei
Y.
5. E
. ~5 . 2 ~ rt , $ ~
.2, ,.,..
. .'~'S ~ ~' :~e k " rJ,r~:. , t ~ . ..
~, si , t~
.','.~ t ~ > 4 ,~ .? .~"'w 3 ..f
a %4
..7.r x ,~5<
~., , . ,
.. '~,.,. $'. ,: 3 ~?.. ...'2'" -~. . R ...,
f , -3x_ ~. .i.~
,,;.g
t
t. y
~r ~ ., .~. .... ~ a
': ~ , 1 ,_:9v . r! .
d"~&.b~s". Y ' :R>.x, .t,'~, .~; f".s..:
~i i
f <.. J1 ? ~' r
vk ~'l. . .,
_ .k::-. -.m .:.;~.~ h ,''
s,.s. .., .. .yr,.. I
, ~Y- ,1. '~::~'~ ;- ~ i .~ t' F.'r-,>
~ . S ~: . , k , -.. ':: .'s . 1
h v s-s.
a, i.
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_~~--i.'
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~...b r %1 :' bi , t ... ,.~ " , p, .'. i..~ tVf t'.
. ,..s
n f,. Y
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m4' c . -~.E-t x4°~. g.'ak, r , . e.i-
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3 S f>'
- ~ . ,~i~-1 s: .u-- ~c,
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.=..,x, E.. 3w,E -"r:
."~Ik~ . ~ 4 , Y x ~>
-g.~,:. < .P.: ._ _ ,'. T ..
Y:~.,y ,1. y
f ,hA.E ~~,_ ~. ..:~T~... c
;3' .' ,;--~r ...:
x'2, , Y
os.1
....'sec .r"$. , a.. -z 3
'~.2a'
,.°.~, tt .>n.. ;~,s -. ~ . ~ .. - , s~
, .r ,
x h .;-.k- r. ,A~_ s,>.ø
f-r>w" -r '
' d. ,. , .J~.-
, ~5 ,
,. -i , ,.k. a .. H: :.: . 1. _'#~' ~ ,x.
.E~, ,
g'; i
r 1~ 4~
'fin.. , .. ,f,, ,:,; "nr'y r'. P'X .,..
h
.~ :r E.~;l2W: ,..Ya z.
- Y~ 't~~~. _ z. a ., i_.,~_ ~,..
CJ~ . .."; . 5, ~E -' ~,. >z,..- ~"- ,~~a
~~ , ~ ~. ~ a~
~K : ,
r
a
~.r~x ~;, a,.>; ~ :-r.:..,~~ ~,s , ~rrr'~,,.-.
.~...c "3~
~:'C,-, ec ; - a,, . , a..:; ~; . ~ . . s"~:.. . :. ~ c~~a. _ r - .~.,. ~- .
.t a ~. . ,.~, '~-,
a35e:.. h., _t'~k~. ,n..dn_x a~uY-, , ~~,_.1 3'4x, _.a5 ~. ."h ~3.._,..>~
"~T'".,t . ~-'.' "
.. ,~_ c '~ .< 3 ..
n .~ - . t
,..,.,are."~ '.~ x-,~, .
~r ,
~;xH.. - ;~_ .. r .~' k .~.. . - r - are . ~. ":u~'.< . -,'a_ . ,e..~E
t ,.~3~
r", ., -E-?~. - < ~ ._' -. ...t... s,:- . ,~ .. ~, t" ,
..,_r~,~;r. ~r~ ~.vr.. i .~ ... , t._,'d .. "r .. ' ':T ; .
. ~ ~ . t, .
r . ~;- >::, ?.." ~" -
., ~, ., .,,y .. r.~,... :..x : . w. s~ ~.. ::.a . ~. ~ ~ . : ~rrf , ~.>...
,..~:. i, . .
s
_ a.... .~,L. , - r~,. ., ,3 ~. r~ . ,L - .~
a~- -. zu~ ,E - ._ i"~~'t
Y- , "3: a - , 4- w 3 _
tx' ."~E..rl....,a...E'r;t' " , k < . , =h, . . a. v.
.. A.m L ;" - ~ ~; ", rd w 1
r rfa' .s.A.,
#5-.-. ..., . tx
8.~~ ~ ., ~.
'. ".',~'. r st ....3r ',.
-t'' xr -. a
. - ua'f ~ --~., a. ~. ,~ ~, .mr . .:. ,, x~a. , . sik -. '~., - 3'. ,..~'-
,sax:< . Em',~'~ ..: .".; r u' r~.~ '~35'~' : ,'..", '~c
., .aaC,..."y,r..,-~, " ~~,..kQ,. =~~; s~,°-:c, .., ,_ ~..a..., ~_
,.~a~.~.~..~-_.<.r. ~;r.-,.. -.:.'r..._ >,. ~~, .. ~.,.-:.a- .. a..f. . u..v..
k'""~,.. _,.=~:
14.5~ 138~ 193~ 138~ 74.8~ 25.4~ 11.8~ 6.80~
Oral Gavage 0 0.44
20.4 135 161 116 83.8 30.9 15.0 7.88
Intraduodenal 101 ~ 242 ~ 261 ~ 162 ~ 82.0 ~ 25.1 ~ 12.2 ~ 11.4 ~
0 0.32
133 147 202 121 66.2 24.2 9.95 5.89
18.2~ 116~ 148~ 128~ 80.0~ 30.0~ 15.7~ 11.6~
Intracolonic 0 0.41
14.7 107 159 144 95.5 34.5 16.1 10.9
*All 1440 minute concentrations are reported as N=2. The concentration of (1R,
2R)-2-
[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochlorideat
1440 minutes for four of the animals (18, 37, 44 and 45) was below the lower
limit of
quantitation.
[0343] Figures 7-10 contain graphical representations of the plasma
concentration versus
time curves for (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride in dog.
[0344] The average AUClast, CmaX and Tmax were similar for all three routes of
(1R, 2R)-2-
[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydrochloride
administration (Tables 3-6). Compared to other dogs used in the study, dog
number 40 had
significantly higher AUClast and CmaX values at all routes tested (Tables 3-
6). The reason for
the higher AUClast and CmaX values in this animal is not apparent from the
available data. The
131
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
observed higher values could be, at least partially due to lower systemic
clearance of (1R,
2R)-2-[(3R)-hydroxypyrrolidinylJ-1-(3,4-dimethoxyphenethoxy)cyclohexane
monohydxochloride in this dog; however, in the absence of intravenous dosing
data, it is not
possible to confirm this hypothesis. Due to this uncertainty, the average
values for AUClast,
Cmax and Tmax were also calculated without data from this animal.
[0345] Administration ofthe (1R, 2R)-2-[(3R)-hydroxypyrrolidinylJ-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride via oral gavage,
intraduodenal or
intracolonic routes resulted in similar AUC/dose values (Figure 11 ) for each
dog used in this
study. Furthermore, average AUClast, Cmax, Tmax and AUC/dose were also similar
for all
three routes of (1R, 2R)-2-[(3R)-hydroxypyrrolidinylJ-1-(3,4-
dimethoxyphenethoxy)
cyclohexane monohydrochloride administration (Figure 10 and Tables 3-6). These
data
suggest that (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride is absorbed approximately
equally
following oral gavage, intraduodenal or colonic administration.
[0346] All references, patents, and patent applications described in this
patent are
incorporated herein by reference to the full extent as though each reference,
patent, or patent
application had been individually incorporated by reference.
Example 4 - Pharmacokinetics of and ion claatarael rrzodulatin coryound
following
sin .le oral administf-ation to male beadle dogs of er 7 days o 4 dail doses
[0347] The purpose of this study was to investigate the pharmacakinetics of
DRUG injection
following single oral administration to male beagle dogs after 7 days of 4
daily doses.
[0348] The ion channel modulating compound applied was (1R,2R)-2-[(3R)-
HydroxypyrrolidinylJ-1-(3,4-dimethoxyphenethoxy) cyclohexane monohydrochloride
(C2oH3iN04.HC1) (referred to as "drug" in this example). This drug was
pxepared and diluted
according to protocol specifications as follows:
Formulation Formulation Formulation Preparation Description
Preparation Use
Group l: DRUG injection solution (10 rnL) was diluted with
Study Day -1 Study Day 1 30 mL of sterile water at a target concentration of 5
mg/mL.
Group 2: DRUG injection solution (16.5 mL) was diluted with
16.5 mL of sterile water at a target concentration of 10 mglmL.
132
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
Group 1: DRUG injection solution (160
mL) was diluted with
Study Day 1 480 mL of sterile water at a target concentration
study Days of 5 mg/mL
2-5 Group 2: DRUG injection solution (264
mL) was diluted with
264 mL of sterile water at a target concentration
of 10 m mL.
Group 1: DRUG injection solution (120
mL) was diluted with
Study Day 5 360 mL of sterile water at a target concentration
Study Days of 5 mg/mL.
6-8 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
Study Day 8 ~ with 35.25 mL of sterile water at a
Study Day 9 target concentration of 5 mg/mL.
Group 2: DRUG injection solution (20 mL)
was diluted with 20 mL of
sterile water at a target concentration
of 10 mg/mL.
[0349] Dose formulation samples (0.1 mL) were collected from each formulation
prior to
dosing on Study 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 l, 2,
5, 7, and 8).
Samples were used to verify the concentration of the dose applied.
[0350] 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-study 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 Study
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).
[0351] On Study Days 1 and 9, 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.
On Study
Days 1 and 9, Group 2 animals received a single dose of prepared drug via oral
gavage at a
target dose level of 10 mg/kg and at a dose volume of 1 mL/kg. On Study Days 2-
8, Group 1
and 2 animals received prepared drug 4 times daily (every 6 hours).
hnmediately following
each dose, 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:
Study ~'oupStudy Dosing Observation
Day NumberNumber
Water flush was not administered
immediately following dose.
(Dose 1 1001 Animal received the water flush
1) following the later doses of
the
same day.
7 I 2 2001 While confirming placement of
1 the gavage tube in the stomach,l
(Dose a red substance was observed in
3) the gavage tube I.
133
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
[0352] Throughout dosing and sample collection, the animals were observed for
any
clinically relevant abnormalities and the following were observed:
Stud CTroupStudyClinical Observation
Da
yy
NumberNumber
_ Excessive salivation was observed
approximately 6 minutes
1 1 1002 post-dose. This condition was not
observed at subsequent
observations.
_ Soft feces (mild) was observed
immediately prior to first dose.
Dose 1 1903 This condition was not observed
1 at subse uent observations.
Emesis (~10 mL of food) was observed
approximately 2 hours
7 1 1001 25 minutes following first dose.
This condition was not
(Dose observed at subse uent observations.
1)
[0353] For Study Days 1 and 9, whole blood samples (1 mL, Heparin
anticoagulant) were
collected from Groups 1 and 2 prior to dosing and at 0.083, 0.25, 0.50, I, 2,
4, 6, 8, and 24
hours post-dose. For Study Days 2-8, whole blood samples were collected prior
to the first
morning dose of each day for Groups 1 and 2. Whole blood samples were placed
in an ice
bath immediately upon collection for processing. A refrigerated centrifuge
{3500 rpm for
~10 minutes at 5~3°C) was used to process whole blood to plasma.
Results
(0354] The concentration of drug in the plasma of the dogs on days I and 9 are
given in the
tables below, and shown graphically in figures I2 and 13.
134
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
Table 17 Drug Assayed concentrating in dog plasma (ng/ml):
Day 1 (Concentration
in ng/ml)
Dog Dog Dog Dog Dog Dog
Time (hrs,)1001 1002 1003 2001 2002 2003
0 BQL BQL BQL BQL BQL BQL
0.083 102 BQL BQL 14.5 10.3 BQL
0.25 683 4.27 5.58 844 861 291
0.5 739 397 128 1620 1190 1070
1 647 291 177 1430 651 979
2 266 135 284 777 301 586
4 71.3 32.7 68.2 203 92.4 210
6 43.9 15.3 27.5 95.7 72.4 104
8 36.3 10.9 22.0 74.7 64.7 60.3
24 2.45 BQL 1.15 9.58 10.5 3.54
** BQL - Below quantitation limit (1 ng/mL)
Day
9
(Concentration
in
ng/ml)
Time Dog Dog Dog Dog Dog Dog
(hrs.)1001 1002 1003 2001 2002 2003
0 342 95.9 277 515 206 526
0.083367 61.2 268 590 229 681
0.25 1300 89.2 608 5150 2410 4660
0.5 1520 613 1370 3510 1840 2570
1 1430 742 1390 2220 1400. 2560
2 1080 409 915 1920 885 1980
4 248 72.3 299 703 227 1070
6 372 84.8 423 566 179 770
8 340 79.4 274 416 226 558
24 37.7 3.72 53.9 29.9 41.4 36.1
'
135
CA 02524034 2005-11-O1
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[0355] Further, the steady-state concentration of drug in blood plasma
immediately before
given another dose of drug is given below:
Table 18: Concentration of drug in dog plasma prior to dosing:
Day Time Dog Dog bog Dog Dog Dog
(hrs.)1001 1002 1003 2001 2002 2003
3 0 290 96.4 217 499 195 523
4 0 515 93.1 164 899 130 541
0 404 80.9 144 349 240 548
6 0 496 110 212 407 266 756
7 0 427 92.3 245 435 200 501
8 0 340 75.7 181 447 226 419
[0356] By day 3, the plasma concentration has reached an approximate steady-
state for all
dogs within both dosing regimes. This data is graphed in Figure 14 (note that
the zero time in
figure 14, is the time immediately before the first morning dosing on the
third day of the
study. Subsequent plasma levels were taken before each morning dose on days 4-
8). Fig. 14
shows the steady-state trough (Cmin) values fox each of the six dogs.
Exa~n~le 5 - Simulated Multiple Dosing Plaarmacokinetics
[0357] This example describes a simulation of the pharmacokinetics of an ion
channel
modulating compound, particularly the phartnacokinetics of different multiple
dosing
regimes. This simulation is based an parameters extracted from experimental
data defining
the plasma levels of one example of an ion channel modulating compound as
described
herein.
[0358] The following parameters were estimated from the pharmacokinetics and
bioavailability of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl)-1-(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride in beagle dogs. A summary of
the
estimated parameters is presented in the table below:
Table 19: Estimated One-Compartment Model Parameters
136
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
l ~Ilodgl~d~l~boc~C~at~~
t?t ~
=
x
<
~
~
F
.
r z ~ r ~ 4 ' ~v't'd~Cf~l'C~'
Par~rneter "- ~ ~c~ TIOa "~ s ~,v~raDev~~tion.
' D~ .2~' , po ~
~~~ 5 3~.~' A -
1.,,.. 4,,
_ Dose m 20 20 20 20 _ 20 0
_/k
Cmax a /mL 3.7 2.7 3.8 2.9 3.3 0.6
Tmaxm_in _15 15 15 15 15 0
U_Cinf a _ 401 259 421 245 332 92
.minlmL
F 91 58 95 55 52 39
%
Ka 0.2 0.2 0.26 0.2 0.215 0.03
Kel 0.0110020.0126030.0103450.0147480.0121750.00196
t1/2 ab 3.5 3.5 2.7 3.5 3.3 0.4
min
t1/2 el 63 55 67 47 58 9
min
Vd Uk 4.1 3.6 4.4 3 3.8 0.6
* Used Tmax equal 15 instead of 30. Using Tmax = 30 causes Vd to be
approximately 2.2 L/kg.
aOne compartment model was found to adequately fit the data. There were not
enough data points to justify a 2
compartment fit.
[0359] All parameters were fit using a one-compartment model, and were in good
agreement
across all four dogs. The parameters from Dog 3 were used in the remainder of
this example
to simulate the pharmacokinetics of (1R, 2R)-2-[(3R)-hydroxypyrrolidinyl]-1-
(3,4-
dimethoxyphenethoxy)cyclohexane monohydrochloride.
[0360] Using the parameters generated, 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.
(0361] The pharmacokinetics (e.g. plasma concentrations over time) of multiple
oral doses
may also be simulated. Figure 16 shows the blood plasma concentration (Cp in
~Cg/ml) for
eight doses of 100 mg of drug administered every 2 hours. The steady state
trough (Cm;n)
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.
(0362] As described herein, dosing regimes may vary, including variations in
the amount of
drug given per dose, the method of dosing (formulation), and the time between
doses. For
example, 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 (Cn,~) is followed by the saw-tooth pattern as the concentration
of the drug
achieves a trough. As before, the trough concentration (Cm;") is approximately
0.92 ~tg/ml.
Figure 18 shows another example in which the loading dose (first dose) is 150
mg, followed
137
CA 02524034 2005-11-O1
WO 2004/098525 PCT/US2004/013731
by maintenance dose (subsequent doses) of 100 mg.
(0363] Drug formulation may also have dramatic effect on the pharmacokinetics
of ion
channel modulating compounds. For example, 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 (see the Immediate
Release and
Controlled Release formulations section, above) 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.
Table 20: First Order Dissolution Rate Constants for IR and CR Formulations
' 111 ~~scriplcc~h
4
F :, ~ ~ S
xr,~ T..
,
~.
x
0.1 IR
11798
0.005728Hydrophilic
0.002366Hydrophilic (300
mg)
0.01333Hydrophobic
0.006189Hot-melt Wax
[0364] Figure 19 shows the pharmacokinetics of these formulations 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.
[0365] 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 xriethods, formulations and routes of administration
to any particular
theory or embodiment.
138
