U.S. patent application number 13/152127 was filed with the patent office on 2011-12-15 for prodrugs of ion channel modulating compounds and uses thereof.
This patent application is currently assigned to Cardiome Pharma Corp.. Invention is credited to Doug Ta Hung Chou, Adewale Eniade, Bertrand M. C. Plouvier.
Application Number | 20110306649 13/152127 |
Document ID | / |
Family ID | 45530779 |
Filed Date | 2011-12-15 |
United States Patent
Application |
20110306649 |
Kind Code |
A1 |
Chou; Doug Ta Hung ; et
al. |
December 15, 2011 |
PRODRUGS OF ION CHANNEL MODULATING COMPOUNDS AND USES THEREOF
Abstract
Prodrugs of ion channeling modulating compounds, including, for
example, prodrugs of the ion channel modulating compound of the
following formula: ##STR00001## are described herein, as well as
methods of making and using such prodrugs and pharmaceutical
compositions containing such prodrugs.
Inventors: |
Chou; Doug Ta Hung;
(Vancouver, CA) ; Eniade; Adewale; (Coquitlam,
CA) ; Plouvier; Bertrand M. C.; (Vancouver,
CA) |
Assignee: |
Cardiome Pharma Corp.
Vancouver
CA
|
Family ID: |
45530779 |
Appl. No.: |
13/152127 |
Filed: |
June 2, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11547423 |
Sep 30, 2008 |
7977373 |
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PCT/US2005/010878 |
Mar 31, 2005 |
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13152127 |
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60586992 |
Jul 8, 2004 |
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60559405 |
Apr 1, 2004 |
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Current U.S.
Class: |
514/424 ;
435/121; 548/541 |
Current CPC
Class: |
C07H 15/203 20130101;
A61P 9/06 20180101; C07D 209/94 20130101; A61K 51/04 20130101; A61K
47/555 20170801; C07D 207/12 20130101; A61K 47/60 20170801; C07F
9/572 20130101; A61K 47/54 20170801; C07D 209/88 20130101; C07B
2200/05 20130101; A61P 37/00 20180101; C07C 257/06 20130101 |
Class at
Publication: |
514/424 ;
548/541; 435/121 |
International
Class: |
A61K 31/4015 20060101
A61K031/4015; C12P 17/10 20060101 C12P017/10; A61P 9/06 20060101
A61P009/06; C07D 207/12 20060101 C07D207/12 |
Claims
1.-25. (canceled)
26. A compound having the following formula: ##STR00070## or a
pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a therapeutically effective amount of a
compound having the following formula: ##STR00071## or a
pharmaceutically acceptable salt thereof.
28. A method of treating or preventing arrhythmia in a subject in
need thereof, wherein the method comprises administering to the
subject a therapeutically effective amount of a compound of claim
26, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition of claim 27.
29. A method for modulating ion channel activity in a subject,
wherein the method comprises administering to the subject a
therapeutically effective amount of a compound of claim 26, or a
pharmaceutically acceptable salt thereof, or a therapeutically
effective amount of a pharmaceutical composition of claim 27.
30. A method of preparing a compound having the following formula:
##STR00072## or a pharmaceutically acceptable salt thereof, wherein
the method comprises treating a compound of formula (PRO-A-Za1):
##STR00073## under standard enzymatic conditions, to provide the
compound having the following formula: ##STR00074## or a
pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/547,423, filed Sep. 30, 2008 (now allowed);
which is a U.S. National Phase Application of International
Application No. PCT/US2005/010878, filed Mar. 31, 2005; which
claims the benefit of U.S. Provisional Patent Application No.
60/586,992, filed Jul. 8, 2004 and Provisional Patent Application
No. 60/559,405, filed Apr. 1, 2004. These applications are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The field of the compounds and methods described herein is
generally prodrugs of ion channel modulating compounds and their
uses, and includes but is not limited to prodrugs of ion channel
modulating compounds and their uses as antiarrhythmics,
particularly for the treatment and/or prevention of atrial
fibrillation (AF) and for the treatment and/or prevention of atrial
flutter.
BACKGROUND OF THE INVENTION
[0003] Ion channels are ubiquitous membrane proteins in the cells
of warm-blooded animals such as mammals. Their critical
physiological roles include control of the electrical potential
across the membrane, mediation of ionic and fluid balance,
facilitation of neuromuscular and neuronal transmission, rapid
transmembrane signal transduction, and regulation of secretion and
contractility.
[0004] For example, cardiac ion channels are proteins that reside
in the cell membrane and control the electrical activity of cardiac
tissue. In response to external stimuli, such as changes in
potential across the cell membrane, these ion channels can form a
pore through the cell membrane, and allow movement of specific ions
into or out of the cell. The integrated behavior of thousands of
ion channels in a single cell results in an ionic current, and the
integrated behavior of many of these ionic currents makes up the
characteristic cardiac action potential.
[0005] Arrhythmia is a variation from the normal rhythm of the
heart beat and generally represents the end product of abnormal
ion-channel structure, number or function. Both atrial arrhythmias
and ventricular arrhythmias are known. The major cause of
fatalities resulting from cardiac arrhythmias is the subtype of
ventricular arrhythmias known as ventricular fibrillation (VF).
Conservative estimates indicate that, in the U.S. alone, each year
over one million Americans will have a new or recurrent coronary
attack (defined as myocardial infarction or fatal coronary heart
disease). About 650,000 of these individuals will be first heart
attacks and 450,000 of these individuals will be recurrent attacks.
About one-third of individuals experiencing these attacks will die
as a result. At least 250,000 people a year die of coronary heart
disease within 1 hour of the onset of symptoms and before they
reach adequate medical aid. These are sudden deaths caused by
cardiac arrest, usually resulting from ventricular
fibrillation.
[0006] Atrial fibrillation (AF) is the most common arrhythmia seen
in clinical practice and is a cause of morbidity in many
individuals (Pritchett E. L., N. Engl. J. Med. 327(14):1031 Oct. 1,
1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(1):264-7
Jan. 1992). The prevalence of AF is likely to increase as the
population ages and it is estimated that 3-5% of patients over the
age of 60 years have AF (Kannel W. B., Abbot R. D., Savage D. D.,
McNamara P. M., N. Engl. J. Med. 306(17):1018-22, 1982; Wolf P. A.,
Abbot R. D., Kannel W. B., Stroke 22(8):983-8, 1991). While AF is
rarely fatal, it can impair cardiac function and is a major cause
of stroke (Hinton R. C., Kistler J. P., Fallon J. T., Friedlich A.
L., Fisher C. M., Am. J. Cardiol. 40(4):509-13, 1977; Wolf P. A.,
Abbot R. D., Kannel W. B., Arch. Intern. Med. 147(9):1561-4, 1987;
Wolf P. A., Abbot R. D., Kannel W. B., Stroke 22(8):983-8, 1991;
Cabin H. S., Clubb K. S., Hall C., Perlmutter R. A., Feinstein A.
R., Am. J. Cardiol. 65(16):1112-6, 1990).
[0007] Antiarrhythmic agents have been developed to prevent or
alleviate cardiac arrhythmia. For example, Class I antiarrhythmic
compounds have been used to treat supraventricular arrhythmias and
ventricular arrhythmias. Treatment of ventricular arrhythmia is
very important since such an arrhythmia can be fatal. Serious
ventricular arrhythmias (ventricular tachycardia and ventricular
fibrillation) occur most often in the presence of myocardial
ischemia and/or infarction. Ventricular fibrillation often occurs
in the setting of acute myocardial ischemia, before infarction
fully develops. At present, there is no satisfactory
pharmacotherapy for the treatment and/or prevention of ventricular
fibrillation during acute ischemia. In fact, many Class I
antiarrhythmic compounds may actually increase mortality in
patients who have had a myocardial infarction.
[0008] Class Ia, Ic and III antiarrhythmic drugs have been used to
convert recent onset AF to sinus rhythm and prevent recurrence of
the arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T.,
Talajic M., Drugs 48(3):345-71, 1994). However, drug therapy is
often limited by adverse effects, including the possibility of
increased mortality, and inadequate efficacy (Feld G. K.,
Circulation 83(6):2248-50, 1990; Coplen S. E., Antman E. M., Berlin
J. A., Hewitt P., Chalmers T. C., Circulation 1991; 83(2):714 and
Circulation 82(4):1106-16, 1990; Flaker G. C., Blackshear J. L.,
McBride R., Kronmal R. A., Halperin J. L., Hart R. G., J. Am. Coll.
Cardiol. 20(3):527-32, 1992; CAST, N. Engl. J. Med. 321:406, 1989;
Nattel S., Cardiovasc. Res. 37(3):567-77, 1998). Conversion rates
for Class I antiarrhythmics range between 50-90% (Nattel S., Hadjis
T., Talajic M., Drugs 48(3):345-71, 1994; Steinbeck G., Remp T.,
Hoffmann E., J. Cardiovasc. Electrophysiol. 9(8 Suppl):S104-8,
1998). Class III antiarrhythmics appear to be more effective for
terminating atrial flutter than for AF and are generally regarded
as less effective than Class I drugs for terminating of AF (Nattel
S., Hadjis T., Talajic M., Drugs 48(3):345-71, 1994; Capucci A.,
Aschieri D., Villani G. Q., Drugs Aging 13(1):51-70, 1998).
Examples of such drugs include ibutilide, dofetilide and sotalol.
Conversion rates for these drugs range between 30-50% for recent
onset AF (Capucci A., Aschieri D., Villani G. Q., Drugs Aging
13(1):51-70, 1998), and they are also associated with a risk of the
induction of Torsades de Pointes ventricular tachyarrhythmias. For
ibutilide, the risk of ventricular proarrhythmia is estimated at
.about.4.4%, with .about.1.7% of patients requiring cardioversion
for refractory ventricular arrhythmias (Kowey P. R., VanderLugt J.
T., Luderer J. R., Am. J. Cardiol. 78(8A):46-52, 1996). Such events
are particularly tragic in the case of AF as this arrhythmia is
rarely a fatal in and of itself.
[0009] There remains a need in the art to identify new
antiarrhythmic treatments, for both ventricular arrhythmias as well
as for atrial arrhythmias. The present invention fulfills this
need, and further provides other related advantages.
RELATED LITERATURE
[0010] Certain ion channel modulating agents are disclosed in PCT
Published Patent Application No. WO 1999/50225; PCT Published
Patent Application No. WO 2000/047547; PCT Published Patent
Application No. WO 2004/098525; PCT Published Patent Application
No. WO 2004/099137; PCT Published Patent Application No. WO
2005/018635; and U.S. Published Patent Application No. WO
2005002693.
SUMMARY OF THE INVENTION
[0011] In one aspect, this invention is directed to prodrugs of ion
channel modulating compounds, wherein the prodrug comprises an ion
channel modulating compound attached to one or more prodrug
moieties.
[0012] In another aspect, this invention is directed to
pharmaceutical compositions comprising prodrugs of ion channel
modulating compounds and pharmaceutically acceptable
excipients.
[0013] In another aspect, this invention is directed to methods of
treating arrhythmia in a subject in need thereof, wherein the
method comprises administering to the subject a therapeutically
effective amount of a prodrug of an ion channel modulating compound
or a pharmaceutical composition comprising an ion channel
modulating compound and a pharmaceutically acceptable
excipient.
[0014] In another aspect, this invention is directed to method for
modulating ion channel activity in a subject in need thereof,
wherein the method comprises administering to the subject a
therapeutically effective amount of a prodrug of an ion channel
modulating compound or a pharmaceutical composition comprising an
ion channel modulating compound and a pharmaceutically acceptable
excipient.
[0015] These aspects are described in more detail below.
DETAILED DESCRIPTION OF THE INVENTION
[0016] As disclosed within the present invention, a variety of
cardiac pathological conditions may be treated and/or prevented by
the use of one or more of the compounds disclosed herein that,
either singly or together with one or more additional therapeutic
agents, are able to selectively inhibit certain combinations of
cardiac ionic currents. More specifically, the cardiac currents
referred to above are the sodium currents and early repolarising
currents.
[0017] Early repolarising currents correspond to those cardiac
ionic currents which activate rapidly after depolarization of
membrane voltage and which effect repolarisation of the cell. Many
of these currents are potassium currents and may include, but are
not limited to, the transient outward current I.sub.to1 such as
Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current
(I.sub.Kur) such as Kv1.5, Kv1.4 and Kv2.1). The ultrarapid delayed
rectifier current (I.sub.Kur) has also been described as I.sub.sus.
A second calcium dependent transient outward current (I.sub.to2)
has also been described.
[0018] The cardiac pathological conditions that may be treated
and/or prevented by the compounds of the present invention may
include, but are not limited to, arrhythmias such as the various
types of atrial and ventricular arrhythmias.
[0019] Of particular interest to the present invention are the ion
channel modulating compounds disclosed in PCT Published Patent
Application No. WO 1999/50225; PCT Published Patent Application No.
WO 2000/047547; PCT Published Patent Application No. WO
2004/098525; PCT Published Patent Application No. WO 2004/099137;
PCT Published Patent Application No. WO 2005/018635; and U.S.
Published Patent Application No. WO 2005002693; the disclosures of
which are incorporated in full herein by reference in their
entireties.
A. DEFINITIONS
[0020] In accordance with the present invention and as used herein,
the following terms are defined to have the following meanings,
unless explicitly stated otherwise:
[0021] "Acyl" refers to branched or unbranched hydrocarbon
fragments terminated by a carbonyl --(C.dbd.O)-- group containing
the specified number of carbon atoms. Examples include acetyl
[CH.sub.3(C.dbd.O)--, a C.sub.2acyl] and propionyl
[CH.sub.3CH.sub.2(C.dbd.O)--, a C.sub.3acyl].
[0022] "Alkanoyloxy" refers to an ester substituent wherein the
ether oxygen is the point of attachment to the molecule. Examples
include propanoyloxy [(CH.sub.3CH.sub.2(C.dbd.O)--O--, a
C.sub.3alkanoyloxy] and ethanoyloxy [CH.sub.3(C.dbd.O)--O--, a
C.sub.2alkanoyloxy].
[0023] "Alkoxy" refers to an O-atom substituted by an alkyl group,
for example, methoxy [--OCH.sub.3, a C.sub.1alkoxy].
[0024] "Alkoxyalkyl" refers to an alkylene group substituted with
an alkoxy group. For example, methoxyethyl
[CH.sub.3OCH.sub.2CH.sub.2--] and ethoxymethyl
(CH.sub.3CH.sub.2OCH.sub.2--] are both C.sub.3alkoxyalkyl
groups.
[0025] "Alkoxycarbonyl" refers to an ester substituent wherein the
carbonyl carbon is the point of attachment to the molecule.
Examples include ethoxycarbonyl [CH.sub.3CH.sub.2O(C.dbd.O)--, a
C.sub.3alkoxycarbonyl] and methoxycarbonyl [CH.sub.3O(C.dbd.O)--, a
C.sub.2alkoxycarbonyl].
[0026] "Alkyl" refers to a branched or unbranched hydrocarbon
fragment containing the specified number of carbon atoms and having
one point of attachment. Examples include n-propyl (a
C.sub.3alkyl), iso-propyl (also a C.sub.3alkyl), and t-butyl (a
C.sub.4alkyl).
[0027] "Alkylene" refers to a divalent radical which is a branched
or unbranched hydrocarbon fragment containing the specified number
of carbon atoms, and having two points of attachment. An example is
propylene [--CH.sub.2CH.sub.2CH.sub.2--, a C.sub.3alkylene].
[0028] "Alkylcarboxy" refers to a branched or unbranched
hydrocarbon fragment terminated by a carboxylic acid group
[--COOH]. Examples include carboxymethyl [HOOC--CH.sub.2--, a
C.sub.2alkylcarboxy] and carboxyethyl [HOOC--CH.sub.2CH.sub.2--, a
C.sub.3alkylcarboxy].
[0029] "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, where phenyl and naphthyl groups are preferred
carbocyclic aryl groups.
[0030] "Aralkyl" refers to an alkylene group wherein one of the
points of attachment is to an aryl group. An example of an aralkyl
group is the benzyl group [C.sub.6H.sub.5CH.sub.2--, a
C.sub.7aralkyl group].
[0031] "Cycloalkyl" refers to a ring, which may be saturated or
unsaturated and monocyclic, bicyclic, or tricyclic formed entirely
from carbon atoms. An example of a cycloalkyl group is the
cyclopentenyl group (C.sub.5H.sub.7--), which is a five carbon
(C.sub.5) unsaturated cycloalkyl group.
[0032] "Carbocyclic" refers to a ring which may be either an aryl
ring or a cycloalkyl ring, both as defined above.
[0033] "Carbocyclic aryl" refers to aromatic groups wherein the
atoms which form the aromatic ring are carbon atoms. Carbocyclic
aryl groups include monocyclic carbocyclic aryl groups such as
phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all
of which may be optionally substituted.
[0034] "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.
[0035] "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, 1968, R. C. Weast, editor; The Chemical
Rubber Co., Cleveland, Ohio. 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.
[0036] "Hydroxyalkyl" refers to a branched or unbranched
hydrocarbon fragment bearing a hydroxy (--OH) group. Examples
include hydroxymethyl (--CH.sub.2OH, a C.sub.1hydroxyalkyl) and
1-hydroxyethyl (--CHOHCH.sub.3, a C.sub.2hydroxyalkyl).
[0037] "Thioalkyl" refers to a sulfur atom substituted by an alkyl
group, for example thiomethyl (CH.sub.3S--, a
C.sub.1thioalkyl).
[0038] "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 described herein. 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.
[0039] As used herein, a "subject" may generally be any human or
non-human animal that would benefit from the methods described in
this application. In one version of the methods, a subject is a
human subject. In some versions of the methods, a subject is a
warm-blooded animal. In some versions of the methods, a subject is
a mammal. In some versions, the subject is any domestic animal,
including, but not limited to dogs and cats. In some versions, the
subject is any livestock animal, including but not limited to
horses, pigs and cattle. In some versions, the subject is any zoo
animal, including but not limited to Bengal tigers.
[0040] As used herein, unless the context makes clear otherwise,
"treatment," and similar word such as "treated," "treating" etc.,
is an approach for obtaining beneficial or desired results,
including, and preferably clinical results. Treatment can involve
optionally either the amelioration of symptoms of the disease or
condition, or the delaying of the progression of the disease or
condition.
[0041] As used herein, unless the context makes clear otherwise,
"prevention," and similar word such as "prevented," "preventing"
etc., is an approach for preventing the onset of a disease or
condition or preventing the occurrence of the symptoms of a disease
or condition, or optionally an approach for delaying the onset of a
disease or condition or delaying the occurrence of the symptoms of
a disease or condition. As used herein, "prevention" and similar
words also includes reducing the intensity, effect, symptoms and/or
burden of a disease or condition prior to onset of the disease or
condition.
[0042] As used herein, an "effective amount" or a "therapeutically
effective amount" of a substance is that amount sufficient to
affect a desired biological effect, such as beneficial results,
including clinical results.
[0043] As used herein, unless the context makes clear otherwise,
"inhibition" and similar words such as "inhibit" of any ion channel
means any decrease in current through that channel. When
"inhibition" is used in the context of a specified concentration,
it is determined by the IC.sub.50. For example, an ion channel
modulating compound which inhibits an ion channel at a
concentration of 1 .mu.M, the ion channel may be said to have an
IC.sub.50 of 1 .mu.M for that ion channel modulating compound. This
example is for illustrative purposes only and is in no way intended
to be limiting.
[0044] As used herein, unless the context makes clear otherwise,
"IC.sub.50" or "IC.sub.50 concentration" means a drug concentration
at which the specified current amplitude (peak or steady-state, or
integrated current) is inhibited by 50%.
[0045] As used herein, unless the context makes clear otherwise,
"blocking" or "block" of an ion channel means any block or
inhibition of current through that ion channel.
[0046] As used herein, unless the context makes clear otherwise,
"recovery time constant of inhibition" refers to a time constant at
which recovery of current amplitude occurs, presumed to reflect
dissociation of a drug from its binding site, as for example, a
sodium channel when the stimulus rate is decreased from 10 Hz to 1
Hz.
[0047] "Pharmaceutically acceptable carriers" for therapeutic use
are well known in the pharmaceutical art, and are described, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing
Co. (current edition). 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 of p-hydroxybenzoic acid may be
added as preservatives. In addition, antioxidants and suspending
agents may be used.
[0048] "Pharmaceutically acceptable salt" refers to salts of a
compound of the invention derived from the combination of such
compounds and a pharmaceutically acceptable organic or inorganic
acid (acid addition salts) or a pharmaceutically acceptable organic
or inorganic base (base addition salts) which retain the biological
effectiveness and properties of the compounds of the present
invention and which are not biologically or otherwise undesirable.
The compounds of the invention described herein may be used in
either the free base or salt forms, with both forms being
considered as being within the scope intended herein.
Pharmaceutically-acceptable salts of the compounds of the invention
include, but are not limited to, amine salts, such as but not
limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline,
ammonia, diethanolamine and other hydroxyalkylamines,
ethylenediamine, N-methylglucamine, procaine,
N-benzylphenethylamine,
1-para-chloro-benzyl-2-pyrrolidin-1'-ylmethylbenzimidazole,
diethylamine and other alkylamines, piperazine and
tris(hydroxymethyl)aminomethane; alkali metal salts, such as but
not limited to lithium, potassium and sodium; alkali earth metal
salts, such as but not limited to barium, calcium and magnesium;
transition metal salts, such as but not limited to zinc, aluminum,
and other metal salts, such as but not limited to sodium hydrogen
phosphate and disodium phosphate; and also including, but not
limited to, salts of mineral acids, such as but not limited to
hydrochloride and sulfates; and salts of organic acids, such as but
not limited to acetates, lactates, malates, tartrates, citrates,
ascorbates, succinates, butyrates, valerates and fumarates. Other
examples of pharmaceutically acceptable salt include 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.
[0049] When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers. Likewise, all tautomeric forms are also intended
to be included.
[0050] It is also to be understood that the compounds described
herein may contain chiral centers. Such chiral centers may be of
either the (R) or (S) configuration, or may be a mixture thereof.
Thus, the compounds provided herein may be enantiomerically pure,
or be stereoisomeric or diastereomeric mixtures. In the case of
amino acid residues, such residues may be of either the L- or
D-form. The configuration for naturally occurring amino acid
residues is generally L. When not specified the residue is the L
form. As used herein, the term "amino acid" refers to .alpha.-amino
acids which are racemic, or of either the D- or L-configuration.
The designation "d" preceding an amino acid designation (e.g.,
dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid.
The designation "dl" preceding an amino acid designation (e.g.,
dlPip) refers to a mixture of the L- and D-isomers of the amino
acid. It is to be understood that the chiral centers of the
compounds provided herein may undergo epimerization in vivo. As
such, one of skill in the art will recognize that administration of
a compound in its (R) form is equivalent, for compounds that
undergo epimerization in vivo, to administration of the compound in
its (S) form.
[0051] For purposes of this invention, when a bond is indicated in
a formula as a wavy line, such as the bond between the oxygen atom
and cyclopentyl moiety in compound of formula (IA), it is meant to
indicate a bond which can give rise to either R or S
stereochemistry.
[0052] Following the standard chemical literature description
practice and as used herein, a full wedge bond means above the ring
plane, and a dashed wedge bond means below the ring plane; one full
bond and one dashed bond (i.e., ----) means a trans configuration,
whereas two full bonds or two dashed bonds means a cis
configuration.
[0053] In the formulae depicted herein, a bond to a substituent
and/or a bond that links a molecular fragment to the remainder of a
compound may be shown as intersecting one or more bonds in a ring
structure. This indicates that the bond may be attached to any one
of the atoms that constitutes the ring structure, so long as a
hydrogen atom could otherwise be present at that atom. Where no
particular substituent(s) is identified for a particular position
in a structure, then hydrogen(s) is present at that position.
[0054] Optically active (+) and (-), (R)- and (S)-, or (D)- and
(L)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques, such as
reverse phase HPLC.
[0055] Thus, in the description of the compounds of formulae (I),
(IA) and (IX) and Compound A, as described herein, all enantiomeric
and diastereomeric forms of the compounds are intended. Pure
stereoisomers, mixtures of enantiomers and/or diastereomers, and
mixtures of different ion channel modulating compounds are
described. The compounds of formulae (I), (IA) and (IX) may
therefore occur as racemates, racemic mixtures and as individual
diastereomers or enantiomers with all isomeric forms being included
in the present invention. A racemate or racemic mixture does not
imply a 50:50 mixture of stereoisomers. Where a given structural
formula or chemical name is presented for a compound of formulae
(I), (IA) and (IX) it is intended that all possible solvates,
pharmaceutically acceptable salts, esters, amides, complexes,
chelates, stereoisomers, geometric isomers, crystalline or
amorphous forms, metabolites, or metabolic precursors of the
compound are also separately described by the chemical structural
formula or chemical name.
[0056] As used herein, substantially pure means sufficiently
homogeneous to appear free of readily detectable impurities as
determined by standard methods of analysis, such as thin layer
chromatography (TLC), gel electrophoresis, high performance liquid
chromatography (HPLC) and mass spectrometry (MS), used by those of
skill in the art to assess such purity, or sufficiently pure such
that further purification would not detectably alter the physical
and chemical properties, such as enzymatic and biological
activities, of the substance. Methods for purification of the
compounds to produce substantially chemically pure compounds are
known to those of skill in the art. A substantially chemically pure
compound may, however, be a mixture of stereoisomers. In such
instances, further purification might increase the specific
activity of the compound.
[0057] The prodrugs of the invention may contain an
"aminocycloalkyl ether moiety", i.e., the following moiety:
##STR00002##
where n is 0, 1, 2, or 3. As used herein, the term "aminocycloalkyl
ether moiety" includes compounds wherein the cycloalkyl group is a
cyclohexyl group, such as in compounds of formula (I), formula (IA)
and Compound A disclosed herein, and includes compounds wherein the
cycloalkyl group is a cyclopentyl, cycloheptyl or cyclooctyl group,
such as in compounds of formula (IX) disclosed herein.
[0058] As used herein, "equivalently inhibits" and "equivalently
inhibited" means equally inhibits or equally inhibited. In one
version, equivalently inhibits means that there is no statistically
significant difference in inhibition of currents resulting from
application of an ion channel modulating compound. For example, the
early and sustained sodium currents are equivalently inhibited if
there is no statistically significant difference in the effect of
an ion channel modulating compound on early and sustained sodium
currents.
[0059] As used herein, "rapidly associated and dissociated" means
that a compound has blocking and unblocking kinetics of the
`fast-on, fast-off` form such as the `fast-on, fast-off` kinetics
defined by Carmeliet and Mubagwa (Prog. Biophys. Molec. Biol. 70,
1-72, 1998). For example, an ion channel modulating compound
rapidly associates and dissociates from sodium channels where the
ion channel modulating compound has `fast-on, fast-off` kinetics as
defined by Carmeliet and Mubagwa.
[0060] As used herein, "rate-independent and use-independent"
inhibition means inhibition that is predominantly heart rate and/or
stimulus rate and use-independent such that there is no
statistically significant effect of steady-state or transient
changes in heart rate or stimulus rate with respect to the
inhibition. For example, an ion channel modulating compound that
inhibits Kv1 channels in a "rate-independent and use-independent"
manner means that there is no influence of the heart rate or
stimulus rate on the amount of inhibition produced by the ion
channel modulating compound on Kv1 channels.
[0061] As used herein, "affects atrial repolarizing currents" means
"has a statistically significant effect on atrial repolarizing
current amplitudes."
[0062] As used herein, "prolongs atrial refractoriness" means "has
a statistically significant prolonging effect on atrial
refractoriness."
[0063] As used herein, "has substantially no effect on ventricular
tissue" means "has no statistically significant effect on normal
human ventricular action potential duration or refractoriness." Any
apparent difference in effect, therefore, is attributed to
intrinsic variability, such as in one aspect, less than a 10%
difference.
[0064] As used herein, "does not substantially slow conduction"
means "has no statistically significant effect on slowing
conduction in the ventricles." As such, any apparent difference in
effect, therefore, is attributed to intrinsic variability. In one
aspect, the ion channel modulating compound has no statistically
significant effect on the slowing of conduction wherein the
compound produces less than a 15%, preferably less than a 10%,
increase in cardiac QRS duration at physiological heart rates.
[0065] As used herein, "rate-dependent inhibition" of an ion
channel means that the level of inhibition of the ion channel
changes with the frequency of stimulation.
[0066] The term "QT interval" is used as is known in the art; for
example, the QT interval as measured from an electrocardiogram. As
used herein, unless the context makes clear otherwise, the term
"prolongs" or "prolong" generally means extends or lengthens as in
duration.
[0067] The term "antiarrhythmic" is used as is known in the art;
for example, as a compound which prevents or alleviates
irregularities in heart rate.
[0068] The term "induces" as used herein, unless the context
indicates otherwise, generally means to stimulate the occurrence
of.
[0069] The term "chemically induced" or "chemically induces" is
used as is known in the art. As used herein, unless the context
makes clear otherwise, the term "terminating" or "terminates"
generally means to bring to an end or to halt.
B. COMPOUNDS OF FORMULA (I), (IA), (IX) AND COMPOUND A
[0070] In one aspect, the prodrugs of the invention comprise an ion
channel modulating compound and a prodrug moiety. 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.
[0071] 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 currents from extracellular loci. Such
compounds act on an external locus of the ion channel that is
accessible from the extracellular surface. This facilitates access
to the ion channel and provides rapid onset kinetics and exhibits
frequency dependent blockade of currents. Such properties are all
beneficial for compounds used to treat arrhythmias. An ion channel
modulating compound may selectively inhibit cardiac early
repolarizing currents and cardiac sodium currents. Ion channel
modulating compounds may be used to selectively inhibit cardiac
early repolarizing currents and cardiac sodium currents under
conditions where an "arrhythmogenic substrate" is present in the
heart. An "arrhythmogenic substrate" is characterized by a
reduction in cardiac action potential duration and/or changes in
action potential morphology, premature action potentials, high
heart rates and may also include increased variability in the time
between action potentials and an increase in cardiac milieu acidity
due to ischaemia or inflammation. Changes such as these are
observed during conditions of myocardial ischaemia or inflammation
and those conditions that precede the onset of arrhythmias such as
atrial fibrillation. 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 may 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.
[0072] 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.
[0073] 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 (I.sub.to)
and/or the ultrarapid delay rectifier current (I.sub.Kur). The
cardiac transient outward potassium current (I.sub.to) and/or the
ultrarapid delay rectifier current (I.sub.Kur) may comprise at
least one of the Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5 currents.
[0074] 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
increase in cardiac milieu acidity. Where the charged form of a
compound is active, its potency increases under conditions
associated with an increase in cardiac milieu acidity.
[0075] 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=1, 2, 3 or 4.
##STR00003##
[0076] 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 and/or 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 an 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
##STR00004##
[0077] where J and K are as described above and groups P and R are
moieties such that there is not substantial rotation about the L-M
bond. In one example P and R are taken together form a cyclic
moiety that prevents substantial rotation about the L-M bond.
[0078] 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.
[0079] In another, the ion channel modulating compound is a
protonated version of any of the ion channel modulating compounds
described herein. That is, for each ion channel modulating compound
described herein, the quaternary protonated amine form of the
compound may also be considered as an amino ion channel modulating
compound. These quaternary protonated amine forms 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
protonated amine forms 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.
[0080] One preferred embodiment of the invention are those prodrugs
wherein the ion channel modulating compound is a compound of
formula (I), or solvates or pharmaceutically acceptable salts
thereof:
##STR00005##
[0081] wherein, independently at each occurrence,
[0082] X is selected from a direct bond, --C(R.sub.6,R.sub.14)--Y--
and --C(R.sub.13).dbd.CH--, with the proviso that when X is a
direct bond and A is formula (III), then at least one of R.sub.7,
R.sub.8 and R.sub.9 is not hydrogen;
[0083] Y is selected from a direct bond, O, S and
C.sub.1-C.sub.4alkylene;
[0084] R.sub.13 is selected from hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl and benzyl;
[0085] R.sub.1 and R.sub.2 are independently selected from
hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8alkoxyalkyl,
C.sub.1-C.sub.8hydroxyalkyl, and C.sub.7-C.sub.12aralkyl; or
[0086] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (I), form a
ring denoted by formula (II):
##STR00006##
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 substituents selected from
hydrogen, hydroxy, C.sub.1-C.sub.3hydroxyalkyl, oxo,
C.sub.2-C.sub.4acyl, C.sub.1-C.sub.3alkyl,
C.sub.2-C.sub.4alkylcarboxy, C.sub.1-C.sub.3alkoxy,
C.sub.1-C.sub.20alkanoyloxy, or may be substituted to form a spiro
five- or six-membered heterocyclic ring containing one or two
heteroatoms selected from oxygen and sulfur; and any two adjacent
additional carbon ring atoms may be fused to a
C.sub.3-C.sub.8carbocyclic ring, and any one or more of the
additional nitrogen ring atoms may be substituted with substituents
selected from hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.4acyl,
C.sub.2-C.sub.4hydroxyalkyl and C.sub.3-C.sub.8alkoxyalkyl; or
[0087] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (I), may form a
bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl,
2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl and
3-azabicyclo[3.2.0]heptan-3-yl;
[0088] R.sub.3 and R.sub.4 are independently attached to the
cyclohexane ring shown in formula (I) at the 3-, 4-, 5- or
6-positions and are independently selected from hydrogen, hydroxy,
C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy, and, when both
R.sub.3 and R.sub.4 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;
[0089] R.sub.5, R.sub.6 and R.sub.14 are independently selected
from hydrogen, C.sub.1-C.sub.6alkyl, aryl and benzyl, or R.sub.6
and R.sub.14, when taken together with the carbon to which they are
attached, may form a spiro C.sub.3-C.sub.5cycloalkyl;
[0090] A is selected from C.sub.5-C.sub.12alkyl, a
C.sub.3-C.sub.13carbocyclic ring, and ring systems selected from
formulae (III), (IV), (V), (VI), (VII) and (VIII):
##STR00007##
where R.sub.7, R.sub.8 and R.sub.9 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl and N(R.sub.15,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl and C.sub.1-C.sub.6alkyl;
##STR00008##
where R.sub.10 and R.sub.11 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl, and N(R.sub.15,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C.sub.1-C.sub.6alkyl;
##STR00009##
where R.sub.12 is selected from bromine, chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl, trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.2-C.sub.7alkoxycarbonyl, C.sub.1-C.sub.6thioalkyl, and
N(R.sub.15,R.sub.16) where R.sub.15 and R.sub.16 are independently
selected from hydrogen, acetyl, methanesulfonyl, and
C.sub.1-C.sub.6alkyl; and Z is selected from CH, CH.sub.2, O, N and
S, where Z may be directly bonded to "X" as shown in formula (I)
when Z is CH or N, or Z may be directly bonded to R.sub.17 when Z
is N, and R.sub.17 is selected from hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl and benzyl;
##STR00010##
[0091] as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof.
[0092] Of particular interest are prodrugs wherein the ion channel
modulating compound of formula (I) is selected from the group
consisting of the following: [0093]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-naphthenethoxy)]cyclohexane;
[0094]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(1-naphthenethoxy)]cyclohexan-
e; [0095]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]cyclohe-
xane; [0096]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy]]cyclohexane;
[0097]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]]cy-
clohexane; [0098]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenethoxy)]cyclohexan-
e; [0099]
(1R,2R)/(1S,2S)-[2-(1-pyrrolidinyl)-1-(1-naphthenethoxy)]cyclohe-
xane; [0100]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-3-yl)]cyclohexa-
ne; [0101]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-4-yl)-
]cyclohexane; [0102]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]cyclohexane;
[0103]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(2-bromophenethoxy)]cyclohexa-
ne; [0104]
(1R,2R)/(1S,2S)-[2-(4-morpholinyl)-1-(3-(3,4-dimethoxyphenyl)pr-
opoxy)]cyclohexane; [0105]
(1R,2R)/(1S,2S)-[2-[bis(2-methoxyethyl)aminyl]-1-(2-naphthenethoxy)]cyclo-
hexane; [0106]
(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-(3,4-dichlorophenethoxy)cyclohexane;
[0107]
(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)cyclohe-
xane; [0108]
(1R,2R)/(1S,2S)-2-(1-acetylpiperazinyl)-1-(2-naphthenethoxy)cyclohexane;
[0109]
(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)c-
yclohexane; [0110]
(1R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1-naphthenethoxy-
)cyclohexane; [0111]
(1R,2S)/(1S,2R)-2-(4-morpholinyl)-1-[(2-trifluoromethyl)phenethoxy]cycloh-
exane monohydrochloride; [0112]
(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-[3-(cyclohexyl)propoxy]cyclohexa-
ne monohydrochloride; [0113]
(1R,2R)/(1S,2S)-2-(3-acetoxypyrrolidinyl)-1-(1-naphthenethoxy)cyclohexane
monohydrochloride; [0114]
(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-[(2,6-dichlorophenyl)methoxy]cyclohex-
ane monohydrochloride; [0115]
(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-[(2,6-dichlorophenyl)methoxy]cyc-
lohexane monohydrochloride; [0116]
(1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclo-
hexane monohydrochloride; [0117]
(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(2,2-diphenylethoxy)cyclohexane
monohydrochloride; [0118]
(1R,2R)/(1S,2S)-2-(3-thiazolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexane
monohydrochloride; [0119]
(1R,2S)/(1S,2R)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)cyclohexane
monohydrochloride; and [0120]
(1R,2R)/(1S,2S)-2-(3-hydroxypyrrolidinyl)-1-(3,4-dimethoxyphenethoxy)cycl-
ohexane monohydrochloride.
[0121] Another preferred embodiment of the prodrugs of the
invention are those prodrugs wherein the ion channel modulating
compound is a compound of formula (IA), or solvates,
pharmaceutically acceptable salts, esters, amides, complexes,
chelates, stereoisomers, stereoisomeric mixtures, geometric
isomers, crystalline or amorphous forms, metabolites, or metabolic
precursors thereof:
##STR00011##
[0122] wherein, R.sub.7, R.sub.8 and R.sub.9 are independently
selected from hydrogen, hydroxy and C.sub.1-C.sub.6alkoxy, as
isolated enantiomeric, diastereomeric and geometric isomers
thereof, and mixtures thereof, with the proviso that R.sub.7,
R.sub.8 and R.sub.9 cannot all be hydrogen.
[0123] Of particular interest are those prodrugs wherein the ion
channel modulating compound of formula (IA) is selected, from the
group consisting of the following: [0124]
(1R,2R)/(1S,2S)-2-[(3R)/(3S)-Hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth-
oxy)-cyclohexane; [0125]
(1R,2R)/(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)--
cyclohexane; [0126]
(1R,2R)/(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)--
cyclohexane; [0127]
(1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0128]
(1R,2R)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0129]
(1R,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0130]
(1R,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0131]
(1S,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0132]
(1S,2R)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0133]
(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; [0134]
(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane; and [0135]
(1R,2S)/(1S,2R)-2-[(3R)/(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxypheneth-
oxy)-cyclohexane.
[0136] Another preferred embodiment of the prodrugs of the
invention are those prodrugs wherein the ion channel modulating
compound is a compound of formula (IX), or solvates or
pharmaceutically acceptable salts thereof:
##STR00012##
[0137] wherein, independently at each occurrence,
[0138] n is selected from 1, 3 and 4;
[0139] Q is either O (oxygen) or --O--C(O);
[0140] X is selected from a direct bond,
--C(R.sub.6,R.sub.14)--Y--, and --C(R.sub.13).dbd.CH--;
[0141] Y is selected from a direct bond, O, S, and
C.sub.1-C.sub.4alkylene;
[0142] R.sub.13 is selected from hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl, and benzyl;
[0143] R.sub.1 and R.sub.2 are independently selected from
hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8alkoxyalkyl,
C.sub.1-C.sub.8hydroxyalkyl, and C.sub.7-C.sub.12aralkyl; or
[0144] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (IX), form a
ring denoted by formula (II):
##STR00013##
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 substituents selected from
hydrogen, hydroxy, C.sub.1-C.sub.3hydroxyalkyl, oxo,
C.sub.2-C.sub.4acyl, C.sub.1-C.sub.3alkyl,
C.sub.2-C.sub.4alkylcarboxy, C.sub.1-C.sub.3alkoxy,
C.sub.1-C.sub.20alkanoyloxy, or may be substituted to form a spiro
five- or six-membered heterocyclic ring containing one or two
heteroatoms selected from oxygen and sulfur; and any two adjacent
additional carbon ring atoms may be fused to a
C.sub.3-C.sub.8carbocyclic ring, and any one or more of the
additional nitrogen ring atoms may be substituted with substituents
selected from hydrogen, C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.4acyl,
C.sub.2-C.sub.4hydroxyalkyl and C.sub.3-C.sub.8alkoxyalkyl; or
[0145] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (IX), 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;
[0146] R.sub.3 and R.sub.4 are independently attached to the
cyclohexane ring shown in formula (IX) at the 3-, 4-, 5- or
6-positions and are independently selected from hydrogen, hydroxy,
C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy, and, when both
R.sub.3 and R.sub.4 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;
[0147] R.sub.5, R.sub.6 and R.sub.14 are independently selected
from hydrogen, C.sub.1-C.sub.6alkyl, aryl and benzyl, or R.sub.6
and R.sub.14, when taken together with the carbon to which they are
attached, may form a spiro C.sub.3-C.sub.5cycloalkyl;
[0148] A is selected from C.sub.6-C.sub.12alkyl, a
C.sub.3-C.sub.13carbocyclic ring, and ring systems selected from
formulae (III), (IV), (V), (VI), (VII) and (VIII):
##STR00014##
where R.sub.7, R.sub.8 and R.sub.9 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl and N(R.sub.16,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl and C.sub.1-C.sub.6alkyl;
##STR00015##
where R.sub.10 and R.sub.11 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl, and N(R.sub.15,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C.sub.1-C.sub.6alkyl;
##STR00016##
where R.sub.12 is selected from bromine, chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl, trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.2-C.sub.7alkoxycarbonyl, C.sub.1-C.sub.6thioalkyl, and
N(R.sub.15,R.sub.16) where R.sub.15 and R.sub.16 are independently
selected from hydrogen, acetyl, methanesulfonyl, and
C.sub.1-C.sub.6alkyl; and Z is selected from CH, CH.sub.2, O, N and
S, where Z may be directly bonded to "X" as shown in formula (IX)
when Z is CH or N, or Z may be directly bonded to R.sub.17 when Z
is N, and R.sub.17 is selected from hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl and benzyl;
##STR00017##
[0149] as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof.
[0150] Of particular interest are those prodrugs wherein the ion
channel modulating compound of formula (IX) is selected from the
group consisting of the following: [0151]
(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-(2-naphthalenethoxy)cyclopentane
monohydrochloride; and [0152]
(1R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(2,6-dichlorophenethoxy)cyclopen-
tane monohydrochloride.
[0153] Another preferred embodiment of the prodrugs of the
invention are those prodrugs wherein the ion channel modulating
compound is Compound A:
##STR00018##
[0154] or pharmaceutically acceptable salts or solvates
thereof.
[0155] This compound has the chemical name of
(1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexa-
ne and is referred to herein as "Compound A". For purposes of this
invention, the term "Compound A" is intended to include this
compound and its pharmaceutically acceptable salts, solvates,
esters, amides, complexes, chelates, stereoisomers, stereoisomeric
mixtures, geometric isomers, crystalline or amorphous forms,
metabolites, or metabolic precursors thereof.
C. PRODRUGS OF ION CHANNEL MODULATING COMPOUNDS
[0156] Prodrugs of ion channel modulating compounds are described
herein. In the sections below, the term "prodrug" refers to a
prodrug of an ion channel modulating compound as described herein.
The term "prodrug(s) of the invention" and "compound(s) of the
invention" are interchangeable herein. Methods for the preparation
of prodrugs and therapeutic uses thereof are also described.
[0157] A prodrug is a modified variation of a parent drug and is
generally biologically inactive at its site of action, but may be
degraded, modified, rearranged, disassociated or cleaved by one or
more enzymatic, non-enzymatic or other in vivo or ex vivo processes
to its parent bioactive form or a derivative thereof, wherein the
derivative generally maintains a bioactive component of the parent
drug but may provide a different bioactive component. A prodrug
generally has a different pharmacokinetic profile than its parent
drug such that, for example, it is more easily absorbed across the
mucosal epithelium, it has better salt formation or solubility
and/or it has better systemic stability (e.g., an increased plasma
half-life).
[0158] Examples of modifications of a parent drug to yield a
prodrug include but are not limited to: (1) ester or amide
derivatives which are susceptible to being cleaved by esterases or
lipases; (2) peptide derivatives which may be recognized by
specific or nonspecific proteases; or (3) derivatives that cause
the prodrug to accumulate at a site of action through membrane
selection; and combinations of the above techniques. Conventional
procedures for the selection and preparation of prodrug derivatives
are described in H. Bundgaard, Design of Prodrugs, (1985), the
contents of which are incorporated herein by reference in its
entirety.
[0159] Any derivative of an ion channel modulating compound that
may be degraded, modified, rearranged, disassociated or cleaved by
one or more enzymatic, non-enzymatic or other in vivo or ex vivo
processes to its parent bioactive form or a variation thereof may
be a prodrug of an ion channel modulating compound. A derivative of
an ion channel modulating compound may be a covalently modified or
non-covalently modified derivative of the compound. Typically, a
derivative is a covalently modified version of an ion channel
modulating compound. A variation of a parent bioactive form
includes any variation of an ion channel modulating compound
wherein less than an entire prodrug moiety but more than no prodrug
moiety are still attached to the ion channel modulating compound
after the prodrug moiety is degraded, modified, rearranged,
dissociated or cleaved. In one variation, a parent ion channel
modulating compound may comprise a carboxylic acid moiety, and when
the carboxylic acid moiety is converted into an ester moiety, the
ester derivative of the ion channel modulating compound may be a
prodrug.
[0160] A prodrug of an ion channel modulating compound may be a
prodrug of any ion channel modulating compound, including compounds
of formula (I), (IA), (IX) and Compound A described herein. A
prodrug of an ion channel modulating compound typically comprises a
prodrug moiety attached to an ion channel modulating compound
either via a direct bond or via a linker.
[0161] A prodrug moiety may be any organic, inorganic or
organometallic moiety, including but not limited to the prodrug
moieties described in the "Prodrug Moieties" section below.
[0162] A prodrug moiety may be attached to an ion channel
modulating compound at any site on the ion channel modulating
compound amenable to its attachment. Sites at which prodrug
moieties may be attached to an ion channel modulating compound to
yield a prodrug include but are not limited to those sites
described in the "prodrug attachment site" section below. A prodrug
moiety may be attached to an ion channel modulating compound either
via a direct bond from the prodrug moiety to the ion channel
modulating compound or via a bond to a linker that is in turn bound
to the ion channel modulating compound. Linkers that may be used in
a prodrug include but are not limited to the linkers described in
the "prodrug linker" section below.
[0163] Typically, a prodrug is formed by the attachment of one
prodrug moiety to an ion channel modulating compound, thereby
producing a prodrug. In this way, a prodrug is provided wherein the
prodrug comprises a 1:1 molar ratio of prodrug moiety to parent ion
channel modulating compound. However, a prodrug may be formed by
the attachment of more than one prodrug moiety to an ion channel
modulating compound. For instance, a prodrug may have a 2:1 or
greater than 2:1 molar ratio of prodrug moiety to parent ion
channel modulating compound.
[0164] In another variation, a prodrug may be formed by the
attachment of more than one ion channel modulating compound to a
single prodrug moiety, thereby producing a prodrug of a ion channel
modulating compound. In another variation, a prodrug is provided
wherein the molar ratio of the ion channel modulating compound to
the prodrug moiety is 2:1 or greater than 2:1, such as 3:1, 4:1 or
greater.
Modification of an Ion Channel Modulating Compound to a Prodrug
[0165] Any ion channel modulating compound may be modified to form
a prodrug of an ion channel modulating compound, including
compounds of formulae (I), (IA) or (IX) and Compound A as described
herein. The ion channel modulating compound to be modified to a
prodrug may increase or decrease ion channel activity of the ion
channel modulating compound. In some instances, the ion channel
modulating compound may be used in the treatment of arrhythmia. In
still other instances, the ion channel modulating compound may be
used in the treatment of atrial fibrillation.
Prodrug Moiety Attachment Site
[0166] A prodrug moiety may be attached to an ion channel
modulating compound at any site on the ion channel modulating
compound that is amenable to such attachment.
[0167] In general, when an ion channel modulating compound is
modified to form a prodrug, at least one valency of the ion channel
modulating compound is substituted with a bond to a prodrug moiety
or with a bond to a linker that is in turn bound to the prodrug
moiety. When a valency is said to be substituted with a bond, it is
meant that any atom, unpaired electron, lone pair of electrons, or
empty electron orbital present in the ion channel modulating
compound may be replaced with a bond to the prodrug moiety or to a
linker. For instance, an ion channel modulating compound comprising
a hydroxyl functional group may form a prodrug by the replacement
of the hydrogen atom of an --OH moiety with a bond to a prodrug
moiety. Accordingly, a prodrug with an --OH moiety is provided.
[0168] An ion channel modulating compound may be attached to a
linker or to the prodrug moiety by any bond, including but not
limited to covalent, ionic, hydrogen, dative, van der Waals, or
other chemical bonding or any combination of chemical bonding. In a
particular version, the ion channel modulating compound is attached
to the prodrug or linker via a covalent bond.
[0169] A functional group on an ion channel modulating compound may
be used to directly attach a prodrug moiety or linker, or may be
converted into a subsequent functional group, which is then
attached to the prodrug moiety or linker. Illustrative examples of
a functional group on an ion channel modulating compound that may
be used for association with a prodrug moiety or linker include but
are not limited to a hydroxyl, an amino, an ether, an ester, a
thio-ester, a thiol, an alkene, an alkyne, an alkyl, a carboxyl, a
ketone, an aldehyde, a thio-aldehyde, a thio-ketone, a
thio-carboxyl, an acyl-halide, a thio-acyl-halide, an alkanoyloxy,
a thio-alkanoyloxy, an alkoxycarbonyl, a thio-alkoxycarbonyl, an
aryl, an aralkyl, an amide, a thio-amide, and a disulfide group. In
one variation, a hydroxyl functionality on an ion channel
modulating compound is used as an attachment site for a prodrug
moiety or linker, for example, to create an ether linkage bond or
an ester or amide linkage bond. In another variation, an amino
functionality on an ion channel modulating compound is used as an
attachment site for a prodrug moiety or linker, for example to
create a quaternary amino linkage bond which may be present as a
quaternary amino salt. In another variation, an ether functionality
on an ion channel modulating compound is used as an attachment site
for a prodrug moiety or linker, for example to create an ether
linkage bond.
Prodrug Moieties
[0170] Any organic, organometallic or inorganic group or atom may
be a prodrug moiety. Typically, a prodrug moiety is selected such
that the prodrug is inactive or less active than the parent ion
channel modulating compound until the prodrug moiety is
disassociated, cleaved, degraded, modified, rearranged or the like,
and the active ion channel modulating compound or a variation
thereof is released. A prodrug moiety may impart on the ion channel
modulating compound any one or a combination of altered
pharmacokinetics, altered drug transport, improved bio-availability
through increased water solubility or increased chemical
stability.
[0171] In one embodiment of the invention, a prodrug moiety is
provided such that the prodrug is an ester derivative of an ion
channel modulating compound. In another variation, a prodrug moiety
is provided such that the prodrug is a carbamate derivative of an
ion channel modulating compound. In still another embodiment, a
prodrug moiety is provided such that the prodrug is an ether
derivative of an ion channel modulating compound.
[0172] In one embodiment of the invention, a prodrug moiety is
provided to enhance the water solubility of the ion channel
modulating compound. A prodrug comprising a water solubility
enhancing moiety typically contains more than one hydroxyl
functional group, and preferably contains 2-6 hydroxyl functional
groups. In one embodiment, a prodrug comprises a water solubility
enhancing moiety such as a monosaccharide, including but not
limited to D- or L-glucose, or a 6-carboxylic acid derivative of a
monosaccharide such as D- or L-glucuronic acid, and D- or
L-gluconic acid, and the like.
[0173] In one embodiment, a prodrug moiety is provided, wherein the
prodrug moiety is selected from the group consisting of:
##STR00019## ##STR00020##
[0174] wherein:
[0175] R' and R'' are independently selected from hydrogen and
C.sub.1-C.sub.6 alkyl;
[0176] each R is independently selected from the group consisting
of hydrogen, alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl and substituted alkynyl;
[0177] R.sup.w is a water-solubilizing moiety;
[0178] each X' is independently selected from O, NH, S or
CH.sub.2;
[0179] n is an integer from 1 to 10; and
[0180] wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl and substituted alkynyl are as defined herein.
Prodrug Linkage Bonds
[0181] When a prodrug moiety is attached to an ion channel
modulating compound, either via a direct bond or via a linker, a
linkage bond is formed that links or attaches the ion channel
modulating compound to the prodrug moiety or linker. Typically, a
linkage bond is a covalent linkage bond, such as a cleavable
covalent bond. The cleavable covalent bond is usually cleaved by
enzymatic or hydrolytic cleavage. Typical covalent linkage bonds
that attach the prodrug moiety to the ion channel modulating
compound include but are not limited to amides, carbamates,
carbonates, ureas, disulfides, sulfonamides, sulfonates,
thio-sulfonates, thio-ethers, thio-esters, ethers, esters, amines
or the like.
[0182] A prodrug moiety may be attached to an ion channel
modulating compound at any site suitable for its attachment, as
discussed above in the section entitled "prodrug attachment site".
Typically, the position on the ion channel modulating compound that
is associated with or attached to a prodrug moiety is a functional
group that, when associated with or attached to the prodrug moiety,
forms a chemical bond that is amenable to enzymatic, non-enzymatic,
non-hydrolytic or hydrolytic cleavage. The functional group on the
ion channel modulating compound may be directly associated with a
prodrug moiety, or may be converted into a subsequent functional
group, which may then be associated with the prodrug moiety.
[0183] Illustrative examples of a functional group on the ion
channel modulating compound that may be used for association with a
prodrug moiety include but are not limited to a hydroxyl, an amino,
an ether, an ester, a thio-ester, a thiol, an alkene, an alkyne, an
alkyl, a carboxyl, a ketone, an aldehyde, a thio-aldehyde, a
thioketone, a thio-carboxyl, an acyl-halide, a thio-acyl-halide, an
alkanoyloxy, thio-alkanoyloxy, an alkoxycarbonyl, a
thio-alkoxycarbonyl, an aryl, an aralkyl, an amide, a thio-amide,
and a disulfide. In one variation, the functional group on the ion
channel modulating compound that is used for association with or
attachment to a prodrug moiety or linker is selected from the group
consisting of an amino, alkoxy or hydroxy group.
Prodrug Linkers
[0184] A prodrug moiety may be attached to an ion channel
modulating compound either directly (i.e. by a direct bond) or via
a linker. Typically, a linker will be attached to an ion channel
modulating compound via a cleavable covalent bond. The cleavable
covalent bond is usually cleaved by enzymatic or hydrolytic
cleavage.
[0185] A linker may be attached to an ion channel modulating
compound via any linkage bond, including but not limited to those
described in the previous section. Typical covalent bonds that
attach a linker to an ion channel modulating compound include but
are not limited to amides, carbamates, carbonates, ureas,
disulfides, sulfonamides, sulfonates, thio-sulfonates, thio-ethers,
thio-esters, ethers, esters, amines, or the like.
[0186] The linker may be of any size, from a small moiety that is
used to facilitate the formation a linkage bond, to a larger group
which is employed as a connector and/or spacer group. These groups
are collectively referred to as "linkers."
[0187] Linkers may be used as a spacer molecule to create a
separation between the ion channel modulating compound and the
prodrug, and/or to avoid undesired steric interactions. The spatial
separation may be desired for modified, enhanced, or optimal
function of the prodrug. The linkers may also facilitate the
preparation or use of the prodrug.
[0188] In synthesizing a prodrug comprising a linker, it may be
useful to employ a linker that has at least two functional groups
(such as a bifunctional linker), one for bonding of the linker to
the ion channel modulating compound and one for bonding of the
linker to the prodrug moiety. A multifunctional linker may also be
used, such that 2, 3, 4 or more prodrug or other moieties may be
attached to a single ion channel modulating compound. In one
variation, a prodrug comprises a linker that is a bifunctional
linker molecule. A bifunctional linker molecule comprises two
reactive termini, one of which is available for linkage to the ion
channel modulating compound and one of which is available for
linkage to the prodrug moiety. The functional groups on the
reactive termini may be the same or different, and are typically
functional groups that are mutually reactive, or complementary to,
reactive functional groups on the ion channel modulating compound
and prodrug moiety that serve as attachment sites for the linker.
Complementary functional groups would be readily recognized by one
of skill in the art and depend upon the ion channel modulating
compound and prodrug moiety for use in the prodrug.
[0189] A linker may be primarily hydrophobic in nature or may be
primarily hydrophilic in nature and may thus contribute to the
overall hydrophobicity or hydrophilicity of the prodrug. A single
linker may also have both hydrophobic and hydrophilic regions
contained within a single linker.
Specific Prodrugs
[0190] In one embodiment of the invention, the prodrug is an ester
derivative of an ion channel modulating compound. An ester
derivative of an ion channel modulating compound is a derivative of
an ion channel modulating compound whereby a prodrug moiety is
attached to the ion channel modulating compound via an ester
linkage. An illustrative schematic diagram of an ester derivative
of an ion channel modulating compound comprising a hydroxyl
functionality is shown below, wherein R is as defined above in the
section "prodrug moieties" In one variation, the ester derivative
is an ester derivative of a compound of formulae (I), (IA) or (IX)
and Compound A as described herein.
##STR00021##
[0191] In another embodiment of the invention, the prodrug is a
carbamate derivative of an ion channel modulating compound. A
carbamate derivative of an ion channel modulating compound is a
derivative of an ion modulating compound whereby a prodrug moiety
is attached to the ion channel modulating compound via a carbamate
linkage. In still another embodiment, the prodrug is an ether
derivative of an ion channel modulating compound. An ether
derivative of an ion channel modulating compound is a derivative of
an ion modulating compound whereby a prodrug moiety is attached to
the ion channel modulating compound via an ether linkage.
[0192] In one embodiment, the prodrug comprises a cycloalkane ring
wherein the cycloalkane ring may be a 5, 6, 7, or 8-membered
cycloalkane ring. In some embodiments, a prodrug comprising a
cycloalkane ring is further substituted with an ether moiety or an
amino moiety or with both an ether and an amino moiety. In a
particular embodiment, a prodrug comprises an amino-substituted
cyclohexyl ether ring. In another embodiment, a prodrug comprises
an amino-substituted cycloalkane ring, wherein the amino group is a
pyrrolidinyl ring that may be optionally substituted, such as with
a hydroxyl group, to provide a prodrug comprising a
hydroxyl-substituted pyrrolidinyl ring. In another embodiment, a
prodrug comprises a compound of formulae (I, (IA) or (IX) and
Compound A as described herein with a prodrug moiety attached
thereto.
[0193] Thus, in one embodiment, prodrugs of compounds of formula
(I), i.e., prodrugs of the following formula (PRO), are
provided:
##STR00022##
[0194] wherein, independently at each occurrence,
[0195] X is selected from a direct bond, --C(R.sub.8,R.sub.14)--Y--
and --C(R.sub.13).dbd.CH--,
[0196] Y is selected from a direct bond, O, S and
C.sub.1-C.sub.4alkylene;
[0197] R.sub.13 is selected from hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl and benzyl;
[0198] R.sub.1 and R.sub.2 are independently selected from
hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8alkoxyalkyl,
C.sub.1-C.sub.8hydroxyalkyl, and C.sub.7-C.sub.12aralkyl; or
[0199] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (PRO-I), form a
ring denoted by formula (PRO-II):
##STR00023##
wherein the ring of formula (PRO-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 substituents selected from
hydrogen, hydroxy, C.sub.1-C.sub.3hydroxyalkyl, oxo,
C.sub.2-C.sub.4acyl, C.sub.1-C.sub.3alkyl,
C.sub.2-C.sub.4alkylcarboxy, C.sub.1-C.sub.3alkoxy,
C.sub.1-C.sub.20alkanoyloxy, or may be substituted to form a spiro
five- or six-membered heterocyclic ring containing one or two
heteroatoms selected from oxygen and sulfur; and any two adjacent
additional carbon ring atoms may be fused to a
C.sub.3-C.sub.8carbocyclic ring, and any one or more of the
additional nitrogen ring atoms may be substituted with substituents
selected from hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.4acyl,
C.sub.2-C.sub.4hydroxyalkyl and C.sub.3-C.sub.8alkoxyalkyl; or
[0200] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (PRO-I), may
form a bicyclic ring system selected from
3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl,
3-azabicyclo[3.1.0]hexan-3-yl and
3-azabicyclo[3.2.0]heptan-3-yl;
[0201] R.sub.3 and R.sub.4 are independently attached to the
cyclohexane ring shown in formula (PRO-I) at the 3-, 4-, 5- or
6-positions and are independently selected from hydrogen, hydroxy,
C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy, and, when both
R.sub.3 and R.sub.4 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;
[0202] R.sub.5, R.sub.6 and R.sub.14 are independently selected
from hydrogen, C.sub.1-C.sub.6alkyl, aryl and benzyl, or R.sub.6
and R.sub.14, when taken together with the carbon to which they are
attached, may form a spiro C.sub.3-C.sub.5cycloalkyl;
[0203] each Z' is independently selected from hydrogen or a prodrug
moiety with the proviso that at least one Z' in the prodrug of
formula (PRO) is a prodrug moiety;
[0204] A is selected from C.sub.8-C.sub.12alkyl, a
C.sub.3-C.sub.13carbocyclic ring, and ring systems selected from
formulae (III), (IV), (V), (VI), (VII) and (VIII):
##STR00024##
where R.sub.7, R.sub.8 and R.sub.9 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl and N(R.sub.18,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl and C.sub.1-C.sub.6alkyl;
##STR00025##
where R.sub.10 and R.sub.11 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl, and N(R.sub.15,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C.sub.1-C.sub.6alkyl;
##STR00026##
where R.sub.12 is selected from bromine, chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl, trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.2-C.sub.7alkoxycarbonyl, C.sub.1-C.sub.6thioalkyl, and
N(R.sub.15,R.sub.16) where R.sub.15 and R.sub.16 are independently
selected from hydrogen, acetyl, methanesulfonyl, and
C.sub.1-C.sub.6alkyl; and Z is selected from CH, CH.sub.2, O, N and
S, where Z may be directly bonded to "X" as shown in formula
(PRO-I) when Z is CH or N, or Z may be directly bonded to R.sub.17
when Z is N, and R.sub.17 is selected from hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, aryl and
benzyl;
##STR00027##
[0205] as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof, or pharmaceutically
acceptable salts or solvates thereof.
[0206] In another embodiment, prodrugs of compounds of formula (I),
i.e., prodrugs of the following formula (PRO-I), are provided:
##STR00028##
[0207] wherein, independently at each occurrence,
[0208] X is selected from a direct bond, --C(R.sub.6,R.sub.14)--Y--
and --C(R.sub.13).dbd.CH--,
[0209] Y is selected from a direct bond, O, S and
C.sub.1-C.sub.4alkylene;
[0210] R.sub.13 is selected from hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl and benzyl;
[0211] R.sub.1 and R.sub.2 are independently selected from
hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8alkoxyalkyl,
C.sub.1-C.sub.8hydroxyalkyl, and C.sub.7-C.sub.12aralkyl; or
[0212] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (PRO-I), form a
ring denoted by formula (PRO-II):
##STR00029##
wherein the ring of formula (PRO-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 substituents selected from
hydrogen, hydroxy, C.sub.1-C.sub.3hydroxyalkyl, oxo,
C.sub.2-C.sub.4acyl, C.sub.1-C.sub.3alkyl,
C.sub.2-C.sub.4alkylcarboxy, C.sub.1-C.sub.3alkoxy,
C.sub.1-C.sub.20alkanoyloxy, or may be substituted to form a spiro
five- or six-membered heterocyclic ring containing one or two
heteroatoms selected from oxygen and sulfur; and any two adjacent
additional carbon ring atoms may be fused to a
C.sub.3-C.sub.8carbocyclic ring, and any one or more of the
additional nitrogen ring atoms may be substituted with substituents
selected from hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.4acyl,
C.sub.2-C.sub.4hydroxyalkyl and C.sub.3-C.sub.8alkoxyalkyl; or
[0213] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (PRO-I), may
form a bicyclic ring system selected from
3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl,
3-azabicyclo[3.1.0]hexan-3-yl and
3-azabicyclo[3.2.0]heptan-3-yl;
[0214] R.sub.3 and R.sub.4 are independently attached to the
cyclohexane ring shown in formula (PRO-I) at the 3-, 4-, 5- or
6-positions and are independently selected from hydrogen, hydroxy,
C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy, and, when both
R.sub.3 and R.sub.4 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;
[0215] R.sub.5, R.sub.6 and R.sub.14 are independently selected
from hydrogen, C.sub.1-C.sub.6alkyl, aryl and benzyl, or R.sub.6
and R.sub.14, when taken together with the carbon to which they are
attached, may form a spiro C.sub.3-C.sub.6cycloalkyl;
[0216] Z' is a prodrug moiety;
[0217] A is selected from C.sub.5-C.sub.12alkyl, a
C.sub.3-C.sub.13carbocyclic ring, and ring systems selected from
formulae (III), (IV), (V), (VI), (VII) and (VIII):
##STR00030##
where R.sub.7, R.sub.8 and R.sub.9 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl and N(R.sub.15,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl and C.sub.1-C.sub.6alkyl;
##STR00031##
where R.sub.10 and R.sub.11 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl, and N(R.sub.16,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C.sub.1-C.sub.6alkyl;
##STR00032##
where R.sub.12 is selected from bromine, chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl, trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.2-C.sub.7alkoxycarbonyl, C.sub.1-C.sub.6thioalkyl, and
N(R.sub.15,R.sub.16) where R.sub.15 and R.sub.16 are independently
selected from hydrogen, acetyl, methanesulfonyl, and
C.sub.1-C.sub.6alkyl; and Z is selected from CH, CH.sub.2, O, N and
S, where Z may be directly bonded to "X" as shown in formula
(PRO-I) when Z is CH or N, or Z may be directly bonded to R.sub.17
when Z is N, and R.sub.17 is selected from hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, aryl and
benzyl;
##STR00033##
[0218] as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof, or pharmaceutically
acceptable salts or solvates thereof.
[0219] In another aspect, one or more prodrug moieties, as defined
herein, may be attached to any suitable position on the compound of
formula (I) to form additional prodrugs of compounds of formula
(I), as illustrated below in the following FIG. 1, where Z', Za and
Zb are each independently a prodrug moiety as described herein, and
each A, X, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are
defined as above for prodrugs of formula (PRO-I):
##STR00034## ##STR00035##
[0220] In another embodiment of the invention, prodrugs of
compounds of formula (IA), i.e., prodrugs of the following formula
(PRO-IA), are provided:
##STR00036##
[0221] wherein:
[0222] Z' is a prodrug moiety; and
[0223] R.sub.7, R.sub.8 and R.sub.9 are independently selected from
hydrogen, hydroxy and C.sub.1-C.sub.6alkoxy, with the proviso that
R.sub.7, R.sub.8 and R.sub.9 cannot all be hydrogen;
[0224] as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof, or pharmaceutically
acceptable salts thereof.
[0225] In another embodiment, one or more prodrug moieties, as
defined herein, may be attached to any suitable position on the
compound of formula (IA) to form additional prodrugs of compounds
of formula (IA), as illustrated below in FIG. 2 where each Z' and
Za are independently a prodrug moiety, and R.sub.7, R.sub.8 and
R.sub.9 are as described above for prodrugs of formula
(PRO-IA):
##STR00037##
[0226] In another embodiment of the invention, prodrugs of
compounds of formula (IX), i.e., prodrugs of the following formula
(PRO-IX), are provided:
##STR00038##
[0227] wherein, independently at each occurrence,
[0228] n is selected from 1, 3 and 4;
[0229] Q is either O (oxygen) or --O--C(O);
[0230] X is selected from a direct bond,
--C(R.sub.6,R.sub.14)--Y--, and --C(R.sub.13).dbd.CH--;
[0231] Y is selected from a direct bond, O, S, and
C.sub.1-C.sub.4alkylene;
[0232] R.sub.13 is selected from hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, aryl, and benzyl;
[0233] R.sub.1 and R.sub.2 are independently selected from
hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.8alkoxyalkyl,
C.sub.1-C.sub.8hydroxyalkyl, and C.sub.7-C.sub.12aralkyl; or
[0234] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (PRO-IX), form
a ring denoted by formula (PRO-II):
##STR00039##
wherein the ring of formula (PRO-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 substituents selected from
hydrogen, hydroxy, C.sub.1-C.sub.3hydroxyalkyl, oxo,
C.sub.2-C.sub.4acyl, C.sub.1-C.sub.3alkyl,
C.sub.2-C.sub.4alkylcarboxy, C.sub.1-C.sub.3alkoxy,
C.sub.1-C.sub.20alkanoyloxy, or may be substituted to form a spiro
five- or six-membered heterocyclic ring containing one or two
heteroatoms selected from oxygen and sulfur; and any two adjacent
additional carbon ring atoms may be fused to a
C.sub.3-C.sub.8carbocyclic ring, and any one or more of the
additional nitrogen ring atoms may be substituted with substituents
selected from hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.4acyl,
C.sub.2-C.sub.4hydroxyalkyl and C.sub.3-C.sub.8alkoxyalkyl; or
[0235] R.sub.1 and R.sub.2, when taken together with the nitrogen
atom to which they are directly attached in formula (PRO-IX), may
form a bicyclic ring system selected from
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;
[0236] R.sub.3 and R.sub.4 are independently attached to the
cyclohexane ring shown in formula (PRO-IX) at the 3-, 4-, 5- or
6-positions and are independently selected from hydrogen, hydroxy,
C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6alkoxy, and, when both
R.sub.3 and R.sub.4 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;
[0237] R.sub.5, R.sub.6 and R.sub.14 are independently selected
from hydrogen, C.sub.1-C.sub.6alkyl, aryl and benzyl, or R.sub.6
and R.sub.14, when taken together with the carbon to which they are
attached, may form a spiro C.sub.3-C.sub.5cycloalkyl;
[0238] Z' is a prodrug moiety;
[0239] A is selected from C.sub.5-C.sub.12alkyl, a
C.sub.3-C.sub.13carbocyclic ring, and ring systems selected from
formulae (III), (IV), (V), (VI), (VII) and (VIII):
##STR00040##
where R.sub.7, R.sub.8 and R.sub.9 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl and N(R.sub.16,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl and C.sub.1-C.sub.6alkyl;
##STR00041##
where R.sub.10 and R.sub.11 are independently selected from
bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy,
hydroxymethyl, methanesulfonamido, nitro, sulfamyl,
trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.7alkoxycarbonyl,
C.sub.1-C.sub.6thioalkyl, and N(R.sub.15,R.sub.16) where R.sub.15
and R.sub.16 are independently selected from hydrogen, acetyl,
methanesulfonyl, and C.sub.1-C.sub.6alkyl;
##STR00042##
where R.sub.12 is selected from bromine, chlorine, fluorine,
carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,
nitro, sulfamyl, trifluoromethyl, C.sub.2-C.sub.7alkanoyloxy,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.2-C.sub.7alkoxycarbonyl, C.sub.1-C.sub.6thioalkyl, and
N(R.sub.15,R.sub.16) where R.sub.15 and R.sub.16 are independently
selected from hydrogen, acetyl, methanesulfonyl, and
C.sub.1-C.sub.6alkyl; and Z is selected from CH, CH.sub.2, O, N and
S, where Z may be directly bonded to "X" as shown in formula
(PRO-IX) when Z is CH or N, or Z may be directly bonded to R.sub.17
when Z is N, and R.sub.17 is selected from hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, aryl and
benzyl;
##STR00043##
[0240] as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof, or pharmaceutically
acceptable salts or solvates thereof.
[0241] In another embodiment of the invention, one or more prodrug
moieties, as defined herein, may be attached to any suitable
position on the compound of formula (IX) to form additional
prodrugs of compounds of formula (PRO-IX), as illustrated below in
the following FIG. 3, where Z', Za and Zb are each independently a
prodrug moiety as described herein, and each n, A, Q, X, R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are defined as above for
prodrugs of formula (PRO-IX):
##STR00044##
[0242] In another embodiment of the invention, prodrugs of Compound
A, i.e., prodrugs of the following formula (PRO-A), are provided
where Z' is a prodrug moiety:
##STR00045##
[0243] where Z' is a prodrug entity;
[0244] or pharmaceutically acceptable salts or solvates
thereof.
[0245] In another aspect, one or more prodrug moieties, as defined
herein, may be attached to other suitable positions on the compound
of formula (A) to form additional prodrugs of compounds of formula
(PRO-A), as illustrated below in the following FIG. 4, where Za and
Zb are each independently a prodrug moiety as described herein:
##STR00046##
[0246] Preparation of the Above Prodrugs of the Invention, and
their Degradation into the respective ion channel modulating
compound of formulae (I), (IA), (IX) or Compound A, is described in
more detail below in the section entitled "Preparation of Prodrugs
of Ion Channel Modulating Compounds".
D. ADMINISTRATION OF THE PRODRUGS OF THE INVENTION
[0247] The present invention provides a composition or medicament
that includes one or more prodrugs of the invention, selected from
any of the compounds, 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, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof, described above, in combination with a
pharmaceutically acceptable carrier, diluent or excipient, and
further provides a method for the manufacture of such a composition
or medicament.
[0248] The present invention further provides a composition or
medicament that includes one or more prodrugs of the invention,
selected from any of the prodrugs, 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, as
isolated enantiomeric, diastereomeric and geometric isomers
thereof, and mixtures thereof, described above, in combination with
appropriate amounts of sodium chloride USP, citric acid USP, sodium
hydroxide NF and water for injection USP, and further provides a
method for the manufacture of such a composition or medicament.
[0249] In other embodiments, the present invention provides a
composition or medicament that includes a compound which is
(1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohex-
ane monohydrochloride, or any solvate thereof; in combination with
appropriate amounts of sodium chloride USP, citric acid USP, sodium
hydroxide NF and water for injection USP; and further provides a
method for the manufacture of such a composition or medicament.
[0250] The present invention further provides a composition or
medicament that includes one or more prodrugs of the invention,
selected from any of the prodrugs, 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, as
isolated enantiomeric, diastereomeric and geometric isomers
thereof, and mixtures thereof, described above, in combination with
appropriate amounts of sodium chloride USP, citric acid USP, sodium
hydroxide NF and water for injection USP, that resulted in an
isotonic intravenous solution of said compound at a concentration
of about 0.1 mg/mL to 100 mg/mL in sodium citrate of about 1 to 400
nM at a pH of about 7.5 to 4.0; and further provides a method for
the manufacture of such a composition or medicament.
[0251] The present invention further provides a composition or
medicament that includes one or more prodrugs of the invention,
selected from any of the prodrugs, or a solvate, pharmaceutically
acceptable salt, ester, amide, complex, chelate, stereoisomer,
stereoisomeric mixture, geometric isomer, crystalline or amorphous
form, metabolite, or metabolic precursor, as isolated enantiomeric,
diastereomeric and geometric isomers thereof, and mixtures thereof,
described above, in combination with appropriate amounts of sodium
chloride USP, citric acid USP, sodium hydroxide NF and water for
injection USP, that resulted in an isotonic intravenous solution of
said compound at a concentration of about 5 mg/mL to 80 mg/mL in
sodium citrate of about 10 to 80 nM at a pH of about 6.5 to 4.5;
and further provides a method for the manufacture of such a
composition or medicament.
[0252] The present invention further provides a composition or
medicament that includes one or more prodrugs of the invention,
selected from any of the prodrugs, or a solvate, pharmaceutically
acceptable salt, ester, amide, complex, chelate, stereoisomer,
stereoisomeric mixture, geometric isomer, crystalline or amorphous
form, metabolite, or metabolic precursor thereof, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof, described above, in combination with appropriate
amounts of sodium chloride USP, citric acid USP, sodium hydroxide
NF and water for injection USP, that resulted in an isotonic
intravenous solution of said compound at a concentration of about
10 mg/mL to 40 mg/mL in sodium citrate of about 20 to 60 nM at a pH
of about 6.0 to 5.0; and further provides a method for the
manufacture of such a composition or medicament.
[0253] The present invention further provides a composition or
medicament that includes one or more prodrugs of the invention,
selected from any of the prodrugs, or a solvate, pharmaceutically
acceptable salt, ester, amide, complex, chelate, stereoisomer,
stereoisomeric mixture, geometric isomer, crystalline or amorphous
form, metabolite, or metabolic precursor thereof, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof, described above, in combination with appropriate
amounts of sodium chloride USP, citric acid USP, sodium hydroxide
NF and water for injection USP, that resulted in an isotonic
intravenous solution of said compound at a concentration of about
20 mg/mL in sodium citrate of about 40 nM at a pH of about 5.5; and
further provides a method for the manufacture of such a composition
or medicament.
[0254] In another embodiment, the present invention provides
compositions which include a compound of the present invention in
admixture or otherwise in association with one or more inert
carriers, excipients and diluents, as well as optional ingredients
if desired. These compositions are useful as, for example, assay
standards, convenient means of making bulk shipments, or
pharmaceutical compositions. An assayable amount of a compound of
the invention is an amount which is readily measurable by standard
assay procedures and techniques as are well known and appreciated
by those skilled in the art. Assayable amounts of a compound of the
invention will generally vary from about 0.001 wt % to about 75 wt
% of the entire weight of the composition. Inert carriers include
any material which does not degrade or otherwise covalently react
with a compound of the invention. Examples of suitable inert
carriers are water; aqueous buffers, such as those which are
generally useful in High Performance Liquid Chromatography (HPLC)
analysis; organic solvents such as acetonitrile, ethyl acetate,
hexane and the like (which are suitable for use in in vitro
diagnostics or assays, but typically are not suitable for
administration to a warm-blooded animal); and pharmaceutically
acceptable carriers, such as physiological saline.
[0255] Thus, the present invention provides a pharmaceutical or
veterinary composition (hereinafter, simply referred to as a
pharmaceutical composition) containing a compound of the present
invention, in admixture with a pharmaceutically acceptable carrier,
excipient or diluent. The invention further provides a
pharmaceutical composition containing an effective amount of
compound of the present invention, in association with a
pharmaceutically acceptable carrier.
[0256] The pharmaceutical compositions of the present invention may
be in any form which allows for the composition to be administered
to a patient. For example, the composition may be in the form of a
solid, liquid or gas (aerosol). Typical routes of administration
include, without limitation, oral, topical, parenteral, sublingual,
rectal, vaginal, and intranasal. The term parenteral as used herein
includes subcutaneous injections, intravenous, intramuscular,
epidural, intrasternal injection or infusion techniques.
Pharmaceutical compositions of the invention are formulated so as
to allow the active ingredients contained therein to be
bioavailable upon administration of the composition to a patient.
Compositions that will be administered to a patient take the form
of one or more dosage units, where for example, a tablet, capsule
or cachet may be a single dosage unit, and a container of the
compound in aerosol form may hold a plurality of dosage units.
[0257] Materials used in preparing the pharmaceutical compositions
should be pharmaceutically pure and non-toxic in the amounts used.
The inventive compositions may include one or more compounds
(active ingredients) known for a particularly desirable effect. It
will be evident to those of ordinary skill in the art that the
optimal dosage of the active ingredient(s) in the pharmaceutical
composition will depend on a variety of factors. Relevant factors
include, without limitation, the type of subject (e.g., human), the
particular form of the active ingredient, the manner of
administration and the composition employed.
[0258] In general, the pharmaceutical composition includes a
compound of the present invention as described herein, in admixture
with one or more carriers. The carrier(s) may be particulate, so
that the compositions are, for example, in tablet or powder form.
The carrier(s) may be liquid, with the compositions being, for
example, an oral syrup or injectable liquid. In addition, the
carrier(s) may be gaseous, so as to provide an aerosol composition
useful in, e.g., inhalatory administration.
[0259] When intended for oral administration, the composition is
preferably in either solid or liquid form, where semi-solid,
semi-liquid, suspension and gel forms are included within the forms
considered herein as either solid or liquid.
[0260] As a solid composition for oral administration, the
composition may be formulated into a powder, granule, compressed
tablet, pill, capsule, cachet, chewing gum, wafer, lozenges, or the
like form. Such a solid composition will typically contain one or
more inert diluents or edible carriers. In addition, one or more of
the following adjuvants may be present: binders such as syrups,
acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose,
ethyl cellulose, microcrystalline cellulose, gum tragacanth or
gelatin, and mixtures thereof; excipients such as starch, lactose
or dextrins, disintegrating agents such as alginic acid, sodium
alginate, Primogel, corn starch and the like; lubricants such as
magnesium stearate or Sterotex; fillers such as lactose, mannitols,
starch, calcium phosphate, sorbitol, methylcellulose, and mixtures
thereof; lubricants such as magnesium stearate, high molecular
weight polymers such as polyethylene glycol, high molecular weight
fatty acids such as stearic acid, silica, wetting agents such as
sodium lauryl sulfate, glidants such as colloidal silicon dioxide;
sweetening agents such as sucrose or saccharin, a flavoring agent
such as peppermint, methyl salicylate or orange flavoring, and a
coloring agent.
[0261] When the composition is in the form of a capsule, e.g., a
gelatin capsule, it may contain, in addition to materials of the
above type, a liquid carrier such as polyethylene glycol or a fatty
oil.
[0262] The composition may be in the form of a liquid, e.g., an
elixir, syrup, solution, aqueous or oily emulsion or suspension, or
even dry powders which may be reconstituted with water and/or other
liquid media prior to use. The liquid may be for oral
administration or for delivery by injection, as two examples. When
intended for oral administration, preferred compositions contain,
in addition to the present compounds, one or more of a sweetening
agent, thickening agent, preservative (e.g., alkyl
p-hydroxybenzoate), dye/colorant and flavor enhancer (flavorant).
In a composition intended to be administered by injection, one or
more of a surfactant, preservative (e.g., alkyl p-hydroxybenzoate),
wetting agent, dispersing agent, suspending agent (e.g., sorbitol,
glucose, or other sugar syrups), buffer, stabilizer and isotonic
agent may be included. The emulsifying agent may be selected from
lecithin or sorbitol monooleate.
[0263] The liquid pharmaceutical compositions of the invention,
whether they be solutions, suspensions or other like form, may
include one or more of the following adjuvants: sterile diluents
such as water for injection, saline solution, preferably
physiological saline, Ringer's solution, isotonic sodium chloride,
fixed oils such as synthetic mono or diglycerides which may serve
as the solvent or suspending medium, polyethylene glycols,
glycerin, propylene glycol or other solvents; antibacterial agents
such as benzyl alcohol or methyl paraben; antioxidants such as
ascorbic acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parenteral preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic. Physiological saline is a preferred
adjuvant. An injectable pharmaceutical composition is preferably
sterile.
[0264] A liquid composition intended for either parenteral or oral
administration should contain an amount of the inventive compound
such that a suitable dosage will be obtained. Typically, this
amount is at least 0.01% of a compound of the invention in the
composition. When intended for oral administration, this amount may
be varied to be between 0.1 and about 70% of the weight of the
composition. Preferred oral compositions contain between about 4%
and about 50% of the active aminocyclohexyl ether compound.
Preferred compositions and preparations according to the present
invention are prepared so that a parenteral dosage unit contains
between 0.01 to 10% by weight of active compound.
[0265] The pharmaceutical composition may be intended for topical
administration, in which case the carrier may suitably comprise a
solution, emulsion, ointment, cream or gel base. The base, for
example, may comprise one or more of the following: petrolatum,
lanolin, polyethylene glycols, bee wax, mineral oil, diluents such
as water and alcohol, and emulsifiers and stabilizers. Thickening
agents may be present in a pharmaceutical composition for topical
administration. If intended for transdermal administration, the
composition may include a transdermal patch or iontophoresis
device. Topical formulations may contain a concentration of the
inventive compound of from about 0.1 to about 25% w/v (weight per
unit volume).
[0266] The composition may be intended for rectal administration,
in the form, e.g., of a suppository which will melt in the rectum
and release the drug. The composition for rectal administration may
contain an oleaginous base as a suitable nonirritating excipient.
Such bases include, without limitation, lanolin, cocoa butter and
polyethylene glycol. Low-melting waxes are preferred for the
preparation of a suppository, where mixtures of fatty acid
glycerides and/or cocoa butter are suitable waxes. The waxes may be
melted, and the aminocyclohexyl ether compound is dispersed
homogeneously therein by stirring. The molten homogeneous mixture
is then poured into convenient sized molds, allowed to cool and
thereby solidify.
[0267] The composition may include various materials which modify
the physical form of a solid or liquid dosage unit. For example,
the composition may include materials that form a coating shell
around the active ingredients. The materials which form the coating
shell are typically inert, and may be selected from, for example,
sugar, shellac, and other enteric coating agents. Alternatively,
the active ingredients may be encased in a gelatin capsule or
cachet.
[0268] The composition in solid or liquid form may include an agent
which binds to the aminocyclohexyl ether compound and thereby
assists in the delivery of the active components. Suitable agents
which may act in this capacity include a monoclonal or polyclonal
antibody, a protein or a liposome.
[0269] The pharmaceutical composition of the present invention may
consist of gaseous dosage units, e.g., it may be in the form of an
aerosol. The term aerosol is used to denote a variety of systems
ranging from those of colloidal nature to systems consisting of
pressurized packages. Delivery may be by a liquefied or compressed
gas or by a suitable pump system which dispenses the active
ingredients. Aerosols of prodrugs of the invention may be delivered
in single phase, bi-phasic, or tri-phasic systems in order to
deliver the active ingredient(s). Delivery of the aerosol includes
the necessary container, activators, valves, subcontainers, and the
like, which together may form a kit. Preferred aerosols may be
determined by one skilled in the art, without undue
experimentation.
[0270] Whether in solid, liquid or gaseous form, the pharmaceutical
composition of the present invention may contain one or more known
pharmacological agents used in methods for either modulating ion
channel activity in a warm-blooded animal or for modulating ion
channel activity in vitro, or used in the treatment and/or
prevention of arrhythmia including atrial/supraventricular
arrhythmia and ventricular arrhythmia, atrial fibrillation,
ventricular fibrillation, atrial flutter, ventricular flutter,
diseases of the central nervous system, convulsion, cardiovascular
diseases (e.g., diseases caused by elevated blood cholesterol or
triglyceride levels), cerebral or myocardial ischemias,
hypertension, long-QT syndrome, stroke, migraine, ophthalmic
diseases, diabetes mellitus, myopathies, Becker's myotonia,
myasthenia gravis, paramyotonia congenita, malignant hyperthermia,
hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune
disorders, graft rejection in organ transplantation or bone marrow
transplantation, heart failure, atrial contractile dysfunction,
hypotension, Alzheimer's disease, dementia and other mental
disorders, alopecia, sexual dysfunction, impotence, demyelinating
diseases, multiple sclerosis, amyotrophic lateral sclerosis,
epileptic spasms, depression, anxiety, schizophrenia, Parkinson's
disease, respiratory disorders, cystic fibrosis, asthma, cough,
inflammation, arthritis, allergies, urinary incontinence, irritable
bowel syndrome, and gastrointestinal disorders such as
gastrointestinal inflammation and ulcer or other diseases. Other
agents known to cause libido enhancement, analgesia or local
anesthesia may be combined with compounds of the present
invention.
[0271] The compositions may be prepared by methodology well known
in the pharmaceutical art. The aminocyclohexyl ether compounds of
the present invention may be in the form of a solvate in a
pharmaceutically acceptable solvent such as water or physiological
saline. Alternatively, the compounds may be in the form of the free
base or in the form of a pharmaceutically acceptable salt such as
the hydrochloride, sulfate, phosphate, citrate, fumarate,
methanesulfonate, acetate, tartrate, maleate, lactate, mandelate,
salicylate, succinate and other salts known in the art. The
appropriate salt would be chosen to enhance bioavailability or
stability of the compound for the appropriate mode of employment
(e.g., oral or parenteral routes of administration).
[0272] A composition intended to be administered by injection can
be prepared by combining the aminocyclohexyl ether compound of the
present invention with water, and preferably buffering agents, so
as to form a solution. The water is preferably sterile pyrogen-free
water. A surfactant may be added to facilitate the formation of a
homogeneous solution or suspension. Surfactants are compounds that
non-covalently interact with the aminocyclohexyl ether compound so
as to facilitate dissolution or homogeneous suspension of the
aminocyclohexyl ether compound in the aqueous delivery system.
Surfactants are desirably present in aqueous compositions of the
invention because the aminocyclohexyl ether compounds according to
the present invention may be hydrophobic. Other carriers for
injection include, without limitation, sterile peroxide-free ethyl
oleate, dehydrated alcohols, propylene glycol, as well as mixtures
thereof.
[0273] Suitable pharmaceutical adjuvants for the injecting
solutions include stabilizing agents, solubilizing agents, buffers,
and viscosity regulators. Examples of these adjuvants include
ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers,
citrate buffers, and high molecular weight polyethylene oxide
viscosity regulators. These pharmaceutical formulations may be
injected intramuscularly, epidurally, intraperitoneally, or
intravenously.
[0274] As used herein, "treating arrhythmia" refers to therapy for
arrhythmia. An effective amount of a composition of the present
invention is used to treat arrhythmia in a warm-blooded animal,
such as a human. Methods of administering effective amounts of
antiarrhythmic agents are well known in the art and include the
administration of an oral or parenteral dosage form. Such dosage
forms include, but are not limited to, parenteral dosage form. Such
dosage forms include, but are not limited to, parenteral solutions,
tablets, capsules, sustained release implants, and transdermal
delivery systems. Generally, oral or intravenous administration is
preferred for some treatments. The dosage amount and frequency are
selected to create an effective level of the agent without harmful
effects. It will generally range from a dosage of from about 0.01
to about 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg
where administered orally or intravenously for antiarrhythmic
effect or other therapeutic application.
[0275] Administration of compositions of the present invention may
be carried out in combination with the administration of other
agents. For example, it may be desired to administer an opioid
antagonist, such as naloxone, if a compound exhibits opioid
activity where such activity may not be desired. The naloxone may
antagonize opioid activity of the administered compound without
adverse interference with the antiarrhythmic activity. As another
example, an aminocyclohexyl ether compound of the invention may be
co-administered with epinephrine in order to induce local
anesthesia.
E. UTILITY AND TESTING OF THE PRODRUGS OF THE INVENTION
[0276] The present invention provides one or more prodrugs of ion
channel modulating compounds, or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above, for use in methods for modulating ion
channel activity in a warm-blooded animal or for modulating ion
channel activity in vitro. In one version of this embodiment, the
warm-blooded animal in which the ion channel activity is modulated
is a mammal; in one version, the warm-blooded animal is a human; in
one version, the warm-blooded animal is a farm animal.
[0277] As disclosed within the present invention, a variety of
cardiac pathological conditions may be treated and/or prevented by
the use of one or more compounds of the present invention or
solvates, pharmaceutically acceptable salts, esters, amides,
complexes, chelates, stereoisomers, stereoisomeric mixtures,
geometric isomers, crystalline or amorphous forms, metabolites, or
metabolic precursors thereof, as isolated enantiomeric,
diastereomeric and geometric isomers thereof, and mixtures thereof;
or a composition or medicament that includes said compound or
mixture comprising compounds as described above. These compounds of
the present invention are ion channel modulating compounds that
either singly or together with one or more additional compounds are
able to selectively modulate certain ionic currents. The ion
currents referred to herein are generally cardiac currents and more
specifically, are the sodium currents and early repolarising
currents.
[0278] Early repolarising currents correspond to those cardiac
ionic currents which activate rapidly after depolarization of
membrane voltage and which effect repolarisation of the cell. Many
of these currents are potassium currents and may include, but are
not limited to, the transient outward current I.sub.to1 such as
Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current
(I.sub.Kur) such as Kv1.5, Kv1.4 and Kv2.1). The ultrarapid delayed
rectifier current (I.sub.Kur) has also been described as I.sub.sus.
A second calcium dependent transient outward current (I.sub.to2)
has also been described.
[0279] The pathological conditions that may be treated and/or
prevented by the present invention may include, but are not limited
to, various cardiovascular diseases.
[0280] The cardiac pathological conditions that may be treated
and/or prevented by the present invention may include, but are not
limited to, arrhythmias such as the various types of atrial and
ventricular arrhythmias, e.g., atrial fibrillation, atrial flutter,
ventricular fibrillation and ventricular flutter.
[0281] In one embodiment, the present invention provides prodrugs
of ion channel modulating compounds that can be used to selectively
inhibit cardiac early repolarising currents and cardiac sodium
currents.
[0282] In another embodiment, the present invention provides
prodrugs of ion channel modulating compounds that can be used to
selectively inhibit cardiac early repolarising currents and cardiac
sodium currents under conditions where an "arrhythmogenic
substrate" is present in the heart. An "arrhythmogenic substrate"
is characterized by a reduction in cardiac action potential
duration and/or changes in action potential morphology, premature
action potentials, high heart rates and may also include increased
variability in the time between action potentials and an increase
in cardiac milieu acidity resulting from 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.
[0283] In other embodiments, the present invention provides a
method for modulating ion channel activity in a warm-blooded animal
comprising administering to a warm-blooded animal in need thereof,
an effective amount of one or more compounds of the present
invention or solvates, pharmaceutically acceptable salts, esters,
amides, complexes, chelates, stereoisomers, stereoisomeric
mixtures, geometric isomers, crystalline or amorphous forms,
metabolites, or metabolic precursors thereof, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof; or a composition or medicament that includes said
compound or mixture comprising compounds as described above.
[0284] In other embodiments, the present invention provides a
method for modulating ion channel activity in an in vitro setting
comprising administering in vitro an effective amount of one or
more prodrugs of the present invention or solvates,
pharmaceutically acceptable salts, esters, amides, complexes,
chelates, stereoisomers, stereoisomeric mixtures, geometric
isomers, crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said prodrug or mixture comprising
compounds as described above.
[0285] In other embodiments, the present invention provides a
method for blocking/inhibiting the activity/conductance of ion
channel in a warm-blooded animal comprising administering to a
warm-blooded animal in need thereof, an effective amount of one or
more prodrugs of the present invention or solvates,
pharmaceutically acceptable salts, esters, amides, complexes,
chelates, stereoisomers, stereoisomeric mixtures, geometric
isomers, crystalline or amorphous forms, metabolites, or metabolic
precursors, as isolated enantiomeric, diastereomeric and geometric
isomers thereof, and mixtures thereof; or a composition or
medicament that includes said prodrug or mixture comprising
compounds as described above.
[0286] In other embodiments, the present invention provides a
method for blocking/inhibiting the activity/conductance of ion
channel in an in vitro setting comprising administering in vitro an
effective amount of one or more prodrugs of the present invention
or solvates, pharmaceutically acceptable salts, esters, amides,
complexes, chelates, stereoisomers, stereoisomeric mixtures,
geometric isomers, crystalline or amorphous forms, metabolites, or
metabolic precursors thereof, as isolated enantiomeric,
diastereomeric and geometric isomers thereof, and mixtures thereof;
or a composition or medicament that includes said compound or
mixture comprising compounds as described above.
[0287] In other embodiments, the present invention provides a
method for modulating potassium ion channel activity in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0288] In other embodiments, the present invention provides a
method for modulating voltage-gated potassium ion channel activity
in a warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, and mixtures thereof; or a composition or
medicament that includes said compound or mixture comprising
compounds as described above.
[0289] In other embodiments, the present invention provides a
method for modulating cardiac sodium currents activity in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, and mixtures thereof; or a composition or
medicament that includes said compound or mixture comprising
compounds as described above.
[0290] In other embodiments, the present invention provides a
method for modulating cardiac early repolarising currents and
cardiac sodium currents ion channel activity in a warm-blooded
animal comprising administering to a warm-blooded animal in need
thereof, an effective amount of one or more compounds of the
present invention or solvates, pharmaceutically acceptable salts,
esters, amides, complexes, chelates, stereoisomers, stereoisomeric
mixtures, geometric isomers, crystalline or amorphous forms,
metabolites, or metabolic precursors thereof, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof; or a composition or medicament that includes said
compound or mixture comprising compounds as described above.
[0291] In other embodiments, the present invention provides a
method for blocking/inhibiting cardiac early repolarising currents
and cardiac sodium currents ion channel activity in a warm-blooded
animal comprising administering to a warm-blooded animal in need
thereof, an effective amount of one or more compounds of the
present invention or solvates, pharmaceutically acceptable salts,
esters, amides, complexes, chelates, stereoisomers, stereoisomeric
mixtures, geometric isomers, crystalline or amorphous forms,
metabolites, or metabolic precursors thereof, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof; or a composition or medicament that includes said
compound or mixture comprising compounds as described above.
[0292] In other embodiments, the present invention provides a
method for blocking/inhibiting the cardiac ion channels responsible
for cardiac early repolarising currents and cardiac sodium currents
ion channel activity in a warm-blooded animal comprising
administering to a warm-blooded animal in need thereof, an
effective amount of one or more compounds of the present invention
or solvates, pharmaceutically acceptable salts, esters, amides,
complexes, chelates, stereoisomers, stereoisomeric mixtures,
geometric isomers, crystalline or amorphous forms, metabolites, or
metabolic precursors thereof, as isolated enantiomeric,
diastereomeric and geometric isomers thereof, and mixtures thereof;
or a composition or medicament that includes said compound or
mixture comprising compounds as described above.
[0293] In other embodiments, the present invention provides a
method for blocking/inhibiting cardiac early repolarising currents
and cardiac sodium currents ion channel activity in a warm-blooded
animal under conditions where an arrhythmogenic substrate is
present in the heart of said warm-blooded animal comprising
administering to a warm-blooded animal in need thereof, an
effective amount of one or more compounds of the present invention
or solvates, pharmaceutically acceptable salts, esters, amides,
complexes, chelates, stereoisomers, stereoisomeric mixtures,
geometric isomers, crystalline or amorphous forms, metabolites, or
metabolic precursors thereof, and mixtures thereof; or a
composition or medicament that includes said compound or mixture
comprising compounds as described above.
[0294] In other embodiments, the present invention provides a
method for blocking/inhibiting the cardiac ion channels responsible
for cardiac early repolarising currents and cardiac sodium currents
ion channel activity in a warm-blooded animal under conditions
where an arrhythmogenic substrate is present in the heart of said
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, and mixtures thereof; or a composition or
medicament that includes said compound or mixture comprising
compounds as described above.
[0295] In other embodiments, the cardiac early repolarising
currents referred to in the present invention comprise ionic
currents which activate rapidly after depolarisation of membrane
voltage and which effect repolarisation of the cell.
[0296] In other embodiments, the cardiac early repolarising
currents referred to in the present invention comprise the cardiac
transient outward potassium current (Ito) and/or the ultrarapid
delayed rectifier current (I.sub.Kur).
[0297] In other embodiments, the cardiac transient outward
potassium current (I.sub.to) and/or the ultrarapid delayed
rectifier current (I.sub.Kur) referred to in the present invention
comprise at least one of the Kv4.2, Kv4.3, Kv2.1, Kv1.4 and Kv1.5
currents.
[0298] In other embodiments, the present invention provides a
method for treating and/or preventing arrhythmia in a warm-blooded
animal comprising administering to a warm-blooded animal in need
thereof, an effective amount of one or more compounds of the
present invention or solvates, pharmaceutically acceptable salts,
esters, amides, complexes, chelates, stereoisomers, stereoisomeric
mixtures, geometric isomers, crystalline or amorphous forms,
metabolites, or metabolic precursors thereof, as isolated
enantiomeric, diastereomeric and geometric isomers thereof, and
mixtures thereof; or a composition or medicament that includes said
compound or mixture comprising compounds as described above.
[0299] In another embodiments, the present invention provides a
method for treating and/or preventing atrial arrhythmia in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0300] In other embodiments, the present invention provides a
method for treating and/or preventing ventricular arrhythmia in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0301] In another embodiments, the present invention provides a
method for treating and/or preventing atrial fibrillation in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0302] In other embodiments, the present invention provides a
method for treating and/or preventing ventricular fibrillation in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0303] In another embodiments, the present invention provides a
method for treating and/or preventing atrial flutter in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0304] In other embodiments, the present invention provides a
method for treating and/or preventing ventricular flutter in a
warm-blooded animal comprising administering to a warm-blooded
animal in need thereof, an effective amount of one or more
compounds of the present invention or solvates, pharmaceutically
acceptable salts, esters, amides, complexes, chelates,
stereoisomers, stereoisomeric mixtures, geometric isomers,
crystalline or amorphous forms, metabolites, or metabolic
precursors thereof, as isolated enantiomeric, diastereomeric and
geometric isomers thereof, and mixtures thereof; or a composition
or medicament that includes said compound or mixture comprising
compounds as described above.
[0305] As noted above, the present invention provides for utilizing
the compounds described above in in vitro and in vivo methods. In
one embodiment, ion channels, such as cardiac potassium channels,
are blocked in vitro or in vivo.
[0306] Ion channels are ubiquitous membrane proteins in the cells
of warm-blooded animals such as mammals. Their critical
physiological roles include control of the electrical potential
across the membrane, mediation of ionic and fluid balance,
facilitation of neuromuscular and neuronal transmission, rapid
transmembrane signal transduction, and regulation of secretion and
contractility.
[0307] Accordingly, compounds that are capable of modulating the
activity or function of the appropriate ion channels will be useful
in treating and/or preventing a variety of diseases or disorders
caused by defective or inadequate function of the ion channels. The
prodrugs of the invention are found to have significant activity in
modulating various ion channel activity both in vivo and in
vitro.
[0308] In one embodiment, the present invention provides a compound
of the present invention or a composition containing said compound,
for use in methods for either modulating ion channel activity in a
warm-blooded animal or for modulating ion channel activity in
vitro. Some of the ion channels to which the compounds,
compositions and methods of the present invention have modulating
effect are various potassium and sodium channels. These potassium
and sodium ion channels may be voltage-activated (also known as
voltage-gated) or ligand-activated (also known as ligand-gated),
and may be present in cardiac and/or neuronal systems.
[0309] In one embodiment, the invention provides a compound of the
present invention, or composition containing said compound, for use
in methods for either modulating activity of ion channel(s) in a
warm-blooded animal or for modulating activity of ion channel(s) in
vitro, wherein said ion channel(s) correspond to some of the
cardiac and/or neuronal ion channels that are responsible for one
or more early repolarising currents comprising those which activate
rapidly after membrane depolarisation and which effect
repolarisation of the cells.
[0310] In another embodiment, of the present invention, the
above-mentioned early repolarising currents comprise the transient
outward potassium current (I.sub.to for cardiac or I.sub.A for
neuronal) and/or the ultrarapid delayed rectifier current
(I.sub.Kur); and include at least one of the Kv4.2, Kv4.3, Kv2.1,
Kv1.3, Kv1.4 and Kv1.5 currents.
[0311] In another embodiment, the present invention provides a
compound of the present invention, or composition containing said
compound, for use in methods for either modulating activity of ion
channel(s) in a warm-blooded animal or for modulating activity of
ion channel(s) in vitro, wherein said ion channel(s) correspond to
either the cardiac or neuronal ion channel(s) that are responsible
for Kv1.5 current.
[0312] In yet another embodiment, the present invention provides a
compound of the present invention, or composition containing said
compound, for use in methods for either modulating activity of ion
channel(s) in a warm-blooded animal or for modulating activity of
ion channel(s) in vitro, wherein said ion channel(s) correspond to
the potassium channel that are responsible for Kv4.2 current.
[0313] Furthermore, the voltage-activated sodium ion channels
comprise the Na.sub.v1, Na.sub.v2 or Na.sub.v3 series and may be
present in cardiac, neuronal, skeletal muscle, central nervous
and/or peripheral nervous systems (e.g., hH1Na).
[0314] For cardiac sodium channels, in studies on ion channels in
isolated human atrial myocytes, compounds of the present invention
have been shown to produce frequency-dependent blockade of cardiac
sodium channels. In these studies enhanced blockade of cardiac
sodium channels was observed at faster rates of stimulation with
sodium block increasing several-fold during rapid stimulation
rates. These protocols have been designed to mimic the short
recovery intervals during fibrillation.
[0315] As noted earlier, modulating the activity of an ion channel
as used above may imply but does not limit to blocking or
inhibiting the conductance of the current through the ion
channel.
[0316] Thus, the present invention provides for methods of treating
a disease or condition in a warm-blooded animal suffering from or
having the disease or condition, and/or preventing a disease or
condition from arising in a warm-blooded animal, wherein a
therapeutically effective amount of a compound of the present
invention, or a composition containing a compound of the present
invention is administered to a warm-blooded animal in need thereof.
Some of the diseases and conditions to which the compounds,
compositions and methods of the present invention may be applied
are as follows: arrhythmia including atrial/supraventricular
arrhythmia and ventricular arrhythmia, atrial fibrillation,
ventricular fibrillation, atrial flutter, ventricular flutter,
diseases of the central nervous system, convulsion, cardiovascular
diseases (e.g., diseases caused by elevated blood cholesterol or
triglyceride levels), cerebral or myocardial ischemias,
hypertension, long-QT syndrome, stroke, migraine, ophthalmic
diseases, diabetes mellitus, myopathies, Becker's myotonia,
myasthenia gravis, paramyotonia congenita, malignant hyperthermia,
hyperkalemic periodic paralysis, Thomsen's myotonia, autoimmune
disorders, graft rejection in organ transplantation or bone marrow
transplantation, heart failure, atrial contractile dysfunction,
hypotension, Alzheimer's disease, dementia and other mental
disorder, alopecia, sexual dysfunction, impotence, demyelinating
diseases, multiple sclerosis, amyotrophic lateral sclerosis,
epileptic spasms, depression, anxiety, schizophrenia, Parkinson's
disease, respiratory disorders, cystic fibrosis, asthma, cough,
inflammation, arthritis, allergies, urinary incontinence, irritable
bowel syndrome, and gastrointestinal disorders such as
gastrointestinal inflammation and ulcer.
[0317] Furthermore, the present invention provides a method for
producing analgesia or local anesthesia in a warm-blooded animal
which includes administering to a warm-blooded animal in need
thereof an effective amount of a compound of the present invention
or a pharmaceutical composition containing said compound. These
methods may be used to relieve or forestall the sensation of pain
in a warm-blooded animal.
[0318] The invention further provides a method for enhancing libido
in a warm-blooded animal which includes administering to a
warm-blooded animal in need thereof an effective amount of a
compound of the present invention or a pharmaceutical composition
containing said compound. These compositions and methods may be
used, for example, to treat a sexual dysfunction, e.g., impotence
in males, and/or to enhance the sexual desire of a patient without
a sexual dysfunction. As another example, the therapeutically
effective amount may be administered to a bull (or other breeding
stock), to promote increased semen ejaculation, where the
ejaculated semen is collected and stored for use as it is needed to
impregnate female cows in promotion of a breeding program.
[0319] Furthermore, the present invention provides a method in an
in vitro setting, wherein a preparation that contains ion channels
is contacted with an effective amount of an aminocyclohexyl ether
compound of the invention. Suitable preparations containing cardiac
sodium channels and/or cardiac potassium channels include cells
isolated from cardiac tissue as well as cultured cell lines. The
step of contacting includes, for example, incubation of ion
channels with a compound under conditions and for a time sufficient
to permit modulation of the activity of the channels by the
compound.
[0320] Administration of compositions of the present invention may
be carried out in combination with the administration of other
agents. For example, it may be desired to administer an opioid
antagonist, such as naloxone, if a compound exhibits opioid
activity where such activity may not be desired. The naloxone may
antagonize opioid activity of the administered compound without
adverse interference with the antiarrhythmic activity. As another
example, an aminocyclohexyl ether compound of the invention may be
co-administered with epinephrine in order to induce local
anesthesia.
[0321] In order to assess whether a compound has a desired
pharmacological activity with the present invention, it may be
subjected to a series of tests. The precise test to employ will
depend on the physiological response of interest. The published
literature contains numerous protocols for testing the efficacy of
a potential therapeutic agent, and these protocols may be employed
with the present compounds and compositions.
[0322] For example, in connection with treatment or prevention of
arrhythmia, a series of four tests may be conducted. In the first
of these tests, a compound of the present invention is given as
increasing (doubling with each dose) intravenous infusion every 5
minutes to a conscious rat. The effects of the compound on blood
pressure, heart rate and the ECG are measured continuously.
Increasing doses are given until a severe adverse event occurs. The
drug related adverse event is identified as being of respiratory,
central nervous system or cardiovascular system origin. This test
gives an indication as to whether the compound is modulating the
activity of sodium channels and/or potassium channels, and in
addition gives information about acute toxicity. The indices of
sodium channel blockade are increasing P-R interval and QRS
widening of the ECG. Potassium channel blockade results in Q-T
interval prolongation of the ECG.
[0323] A second test involves administration of a compound as an
infusion to pentobarbital anesthetized rats in which the left
ventricle is subjected to electrical square wave stimulation
performed according to a preset protocol described in further
detail below. This protocol includes the determination of
thresholds for induction of extrasystoles and ventricular
fibrillation. In addition, effects on electrical refractoriness are
assessed by a single extra beat technique. In addition effects on
blood pressure, heart rate and the ECG are recorded. In this test,
sodium channel blockers produce the ECG changes expected from the
first test. In addition, sodium channel blockers also raise the
thresholds for induction of extrasystoles and ventricular
fibrillation. Potassium channel blockade is revealed by increasing
refractoriness and widening of the Q-T intervals of the ECG.
[0324] A third test involves exposing isolated rat hearts to
increasing concentrations of a compound. Ventricular pressures,
heart rate, conduction velocity and ECG are recorded in the
isolated heart in the presence of varying concentrations of the
compound. The test provides evidence for direct toxic effects on
the myocardium. Additionally, selectivity, potency and efficacy of
action of a compound can be ascertained under conditions simulating
ischemia. Concentrations found to be effective in this test are
expected to be efficacious in the electrophysiological studies.
[0325] A fourth test is estimation of the antiarrhythmic activity
of a compound against the arrhythmias induced by coronary artery
occlusion in anaesthetized rats. It is expected that a good
antiarrhythmic compound will have antiarrhythmic activity at doses
which have minimal effects on either the ECG, blood pressure or
heart rate under normal conditions.
[0326] All of the foregoing tests may be performed using rat
tissue. In order to ensure that a compound is not having effects
which are only specific to rat tissue, further experiments may be
performed in dogs and primates. In order to assess possible sodium
channel and potassium channel blocking action in vivo in dogs, a
compound is tested for effects on the ECG, ventricular epicardial
conduction velocity and responses to electrical stimulation. An
anesthetized dog is subjected to an open chest procedure to expose
the left ventricular epicardium. After the pericardium is removed
from the heart a recording/stimulation electrode is sewn onto the
epicardial surface of the left ventricle. Using this array, and
suitable stimulation protocols, conduction velocity across the
epicardium as well as responsiveness to electrical stimulation can
be assessed. This information coupled with measurements of the ECG
allows one to assess whether sodium and/or potassium channel
blockade occurs. As in the first test in rats, a compound is given
as a series of increasing bolus doses. At the same time possible
toxic effects of a compound on the dog's cardiovascular system is
assessed.
[0327] The effects of a compound on the ECG and responses to
electrical stimulation are also assessed in intact, anesthetized
monkeys (Macaca fascicularis). In this preparation, a blood
pressure cannula and ECG electrodes are suitably placed in an
anesthetized monkey. In addition, a stimulating electrode is placed
onto the right atria and/or ventricle, together with monophasic
action potential electrode. As in the tests described above, ECG
and electrical stimulation response to a compound reveal the
possible presence of sodium and/or potassium channel blockade. The
monophasic action potential also reveals whether a compound widens
the action potential, an action expected of a potassium channel
blocker.
[0328] As another example, in connection with the mitigation or
prevention of the sensation of pain, the following test may be
performed. To determine the effects of a compound of the present
invention on an animal's response to a sharp pain sensation, the
effects of a slight prick from a 7.5 g weighted syringe fitted with
a 23 G needle as applied to the shaved back of a guinea pig (Cavia
porcellus) is assessed following subcutaneous administration of
sufficient (50 .mu.L, 10 mg/mL) solution in saline to raise a
visible bleb on the skin. Each test is performed on the central
area of the bleb and also on its periphery to check for diffusion
of the test solution from the point of administration. If the test
animal produces a flinch in response to the stimulus, this
demonstrates the absence of blockade of pain sensation. Testing may
be carried out at intervals for up to 8 hours or more
post-administration. The sites of bleb formation are examined after
24 hours to check for skin abnormalities consequent to local
administration of test substances or of the vehicle used for
preparation of the test solutions.
F. PREPARATION OF THE COMPOUNDS OF FORMULA (I), (IA), (IX) AND
COMPOUND A
[0329] The ion channel modulating compounds of formulae (I), (IA)
and/or (IX) and/or Compound A used in the present invention may be
prepared as described in PCT Published Patent Application No. WO
1999/50225; PCT Published Patent Application No. WO 2000/047547;
PCT Published Patent Application No. WO 2004/098525; PCT Published
Patent Application No. WO 2004/099137; PCT Published Patent
Application No. WO 2005/018635; and U.S. Published Patent
Application No. WO 2005002693; or may be prepared by methods known
to one skilled in the art.
G. PREPARATION OF PRODRUGS OF ION CHANNEL MODULATING COMPOUNDS
[0330] The prodrugs of ion channel modulating compounds described
above are generally prepared by treating the respective ion channel
modulating compound, in particular, a compound of formula (I),
formula (IA), formula (IX) or Compound A, with a chemical entity
allowing for the attachment of the Z', Za, or Zb group to the ion
channel modulating compound. The methods may comprise of
conjugation of an ion channel modulating compound to an additional
drug moiety via a linker. The scheme below for compounds of formula
(I) is generally applicable to all ion channel modulating compounds
described above which comprise an aminocycloalkyl ether moiety. In
the scheme below, Z', Za' and Zb represent prodrug moieties as
described herein.
##STR00047##
[0331] The prodrugs described herein may be in the form of a
pharmaceutically acceptable salt. In one variation, the prodrug
comprises a quaternary amine salt.
[0332] Upon administration of the compound to a subject, the
prodrugs of the invention undergo an enzymatic degradation to
produce the corresponding ion channel modulating compound,
particularly the compound of formula (I), formula (IA), formula
(IX) or Compound A as described above and in more detail below.
[0333] In general, a prodrug of the invention may be formed by the
reaction of a prodrug moiety or linker with an ion channel
modulating compound under conditions appropriate to form a linkage
bond between the ion channel modulating compound and the prodrug
moiety or linker. If a linker is used, a subsequent step of
reacting a prodrug moiety with the linker under conditions
appropriate to attach the prodrug moiety to the linker may be
required, or alternatively, the attachment of the prodrug moiety to
the linker may take place prior to attachment of the linker to the
ion channel modulating compound.
[0334] It is understood that in the following description,
combinations of substituents and/or variables of any depicted
formulae are permissible only if such contributions result in
stable compounds.
[0335] It will also be appreciated by those skilled in the art that
in the processes described below the functional groups of
intermediate compounds may need to be protected by suitable
protecting groups. Such functional groups include hydroxy, amino,
mercapto and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl or diarylalkylsilyl (e.g.,
t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),
tetrahydropyranyl, benzyl, and the like. Suitable protecting groups
for amino, amidino and guanidino include t-butoxycarbonyl,
benzyloxycarbonyl, and the like. Suitable protecting groups for
mercapto include --C(O)--R'' (where R'' is alkyl, aryl or
arylalkyl), p-methoxybenzyl, trityl and the like. Suitable
protecting groups for carboxylic acid include alkyl, aryl or
arylalkyl esters.
[0336] Protecting groups may be added or removed in accordance with
standard techniques, which are well-known to those skilled in the
art and as described herein.
[0337] The use of protecting groups is described in detail in
Green, T. W. and P. G. M. Wutz, Protective Groups in Organic
Synthesis (1999), 3rd Ed., Wiley. The protecting group may also be
a polymer resin such as a Wang resin or a 2-chlorotrityl-chloride
resin.
[0338] It will also be appreciated by those skilled in the art,
although such protected derivatives of compounds of this invention
may not possess pharmacological activity as such, they may be
administered to a mammal and thereafter metabolized in the body to
form compounds of the invention which are pharmacologically active.
Such derivatives may therefore be described as "prodrugs". All
prodrugs of compounds of this invention are included within the
scope of the invention.
[0339] The following Reaction Schemes illustrate methods to make
compounds of this invention. It is understood that one of those
skilled in the art would be able to make these compounds by similar
methods or by methods known to one skilled in the art. In general,
starting components may be obtained from sources such as Sigma
Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific,
TCI, and Fluorochem USA, etc. or synthesized according to sources
known to those skilled in the art (see, e.g., Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 5th edition
(Wiley, December 2000)) or prepared as described in this invention.
If applicable, the following parameters were determined:
[0340] Melting points were determined on a Fisher-Johns apparatus
and are uncorrected. NMR spectra were acquired in the indicated
solvent on a Brucker AC-200, Varian XL-300, Brucker AV-300 or
AV-400. Mass spectra were recorded for E1 on a Kratos MS50, for
FAB/LSIMS on a Kratos Concept IIHQ and for ES on a Micromass
(Waters) Quattro (I) MSMS, connected to a HP1090 Series 2 LC
(Agilent), controlled by Masslynx version 3.3 software. Elemental
analyses were performed on an Element Analyzer 1108 by D. & H.
Malhow, University of Alberta, Edmonton, AB (where analyses were
indicated only by symbols of the elements, analytical results were
within .+-.0.4% of the theoretical values). Whenever elemental
analyses were not available, purity was determined by HPLC and
capillary electrophoresis (CE). HPLC analyses were performed using
a Gilson HPLC system (Gilson, Middleton, Wis.) with UV detection at
200 nm. A C.sub.18 column with 150.times.4.6 mm, 5.mu. particle
size was used. The mobile phase was delivered isocratically or as a
gradient at a flow rate of 1 mL/min and consisted of a combination
of phosphate buffer (low or high pH) and acetonitrile. Samples were
prepared at .about.100 .mu.g/mL in mobile phase and 20 .mu.L were
injected into the HPLC. Purity was expressed in area %. CE analyses
were performed using a P/ACE System MDQ (Beckman Coulter,
Fullerton, Calif.). Uncoated silica capillaries with 60 (50 to
detector) cm length and 75 .mu.m internal diameter were used. The
run buffer used was 100 mM sodium phosphate (pH 2.5). The
separation voltage was either 23 or 25 kV (normal polarity) and the
capillary cartridge temperature was maintained at 20.degree. C.
Samples (.about.0.5 mg/mL in water) were injected by pressure at
0.5 psi for 6 seconds. Detection was by UV at 200 or 213 nm. Purity
was expressed in area %. IR spectral data were recorded on a
Perkin-Elmer 983G spectrophotometer. Optical rotations were
performed by F. Hoffman-La Roche Ltd (CH, Basel). Thin layer
chromatography (TLC) was performed on E. Merck, TLC aluminum sheets
20.times.20 cm, Silica gel 60 F.sub.254 plates. Flash
chromatography was performed on E.M. Science silica gel 60 (70-230
mesh). Dry flash chromatography was performed with Sigma silica gel
type H. Chromatotron chromatography (Harisson Research, USA) was
performed on 4 mm plate with EM Science silica gel 60P F.sub.254
with Gypsum or aluminum oxide 60P F.sub.254 with Gypsum (type E).
Preparative HPLC were performed on a Waters Delta Prep 4000 with a
cartridge column (porasil, 10 .mu.m, 125 .ANG., 40 mm.times.100
mm). GC analyses were performed on a Hewlett Packard HP 6890
equipped with 30 m.times.0.25 mm.times.0.25 .mu.m capillary column
HP-35 (crosslinked 35% PH ME siloxane) and a flame-ionization
detector. High-boiling solvents (DMF, DMSO) were Sure/Seal.TM. from
Aldrich, and tetrahydrofuran (THF) and ethylene glycol dimethyl
ether (DME) were distilled from sodium-benzophenone ketyl. Organic
extracts were dried with Na.sub.2SO.sub.4 unless otherwise noted.
All moisture sensitive reactions were performed in dried glassware
under a nitrogen or argon atmosphere.
[0341] Although anyone skilled in the art is capable of preparing
the compounds of the invention according to the general techniques
disclosed above, more specific details on synthetic techniques for
compositions of the invention are provided elsewhere in this
specification for convenience. Again, all reagents and reaction
conditions employed in synthesis are known to those skilled in the
art and are available from ordinary commercial sources.
[0342] The syntheses of compounds of this invention and their
degradation into the respective ion channel modulating compounds
are illustrated by, but not limited to the following examples and
reaction schemes.
Example 1
[0343] The following Reaction Scheme 1 illustrates the
intramolecular cyclization-elimination reaction transformation of a
carbamate derivative prodrug of the present invention (PRO-A1) to
the respective Compound A and prodrug moiety:
##STR00048##
[0344] Reaction Scheme 1 shows a transformation process that may
occur in the release of an ion channel modulating compound, such as
Compound A, from a prodrug, such as the prodrug of formula
(PRO-A1). In this example, an intramolecular
cyclization-elimination reaction transformation is depicted. In
this way, generation of the parent ion channel modulating compound,
such as Compound A, does not only depend upon the host
environments, but may also normally depend upon the rate of the
cyclization reaction, which generally depends on factors such as:
pH of the environment, length of the linkage between the two
nitrogen atoms (NR' and NHR'') and, the nature of the R' and R''
groups on the nitrogen atoms (NR' and NHR'' as reported by Saari et
al. (Saari, W. S.; Schwering, J. E.; Lyle, P. A.; Smith, S. J.;
Engelhardt, E. L. J. Med. Chem. 1990, 33, 97-101), a series of
basic carbamates of 4-hydroxyanisole was synthesized and evaluated
as progenitors of this melanocytotoxic phenol. In all cases,
4-hydroxyanisole was generated cleanly but at different rates
depending upon the structure of the specific carbamate.
Furthermore, kinetic data indicated that the hydrolysis rate
follows first-order kinetics).)
[0345] In Reaction Scheme 1, which is generally applicable to
prodrugs comprising a carbamate derivative of an ion channel
modulating compound, R' and R'' in the carbamate linker functional
group of the prodrug of formula (PRO-A1) are selected from hydrogen
or C.sub.1-C.sub.6-alkyl. In one aspect, R' and R'' of the prodrug
of formula (PRO-A1) are both methyl groups.
[0346] Synthesis of a prodrug, such as that shown above in formula
(PRO-A1) with the basic carbamate linker functional group may be
carried out according to a process shown below in Reaction Scheme
1A. The process is generally applicable for any ion channel
modulating compound comprising a hydroxyl functionality, although
alternate processes may also be carried out.
##STR00049##
[0347] In the first step of Reaction Scheme 1A, activation of the
3-pyrrolidinol functionality of Compound A to carbonate (PRO-A2)
with 4-nitrophenyl chloroformate (PRO-1) may be carried out in a
mixture of anhydrous THF-dichloromethane in the presence of
pyridine (3 equiv.) at 0.degree. C. for 2 h and then at ambient
temperature for 18 h (see, de Groot, F. M. H. et al. J. Org. Chem.
2001, 66, 8815-8830). Reaction of carbonate (PRO-A2) with
BOC-protected diamines (PRO-2) in the presence of
N,N-diisopropylamine (1 equiv.) in THF at 0.degree. C. for 30 min
and then at ambient temperature for a further 20 h may result in
the formation of the BOC-protected carbamate (PRO-A3).
Monoprotected diamine intermediates (PRO-2) which could ultimately
be deblocked in the last step without destruction of the carbamate
functionality may be prepared according to literature methods (see,
Saari, W. S.; Schwering, J. E.; Lyle, P. A.; Smith, S. J.;
Engelhardt, E. L. J. Med. Chem. 1990, 33, 97-101). The
tert-butoxycarbonyl (BOC) group may be used for that approach.
Syntheses of mono-alkoxycarbonyl-protected diamines are extensively
reported in the literature (Hansen, J. B.; Nielsen, M. C.; Erhbar,
U.; Buchardt, O. Synthesis 1982, 404; Fuchs, S.; Klinger, W.;
Voelter, W. Liebigs Ann. Chem. 1977, 602; Geiger, R. Justus Liebigs
Ann. Chem. 1971, 750, 165; Herrin, T. R.; Pauvlik, J. M.; Schuber,
E. V.; Geiszler, A. O. J. Med. Chem. 1975, 18, 1216; Houssin, R.;
Bernier, J. L.; Henichart, J.-P. Synthesis 1988, 259; Atwell, G.
J.; Denny, W. A. Synthesis 1984, 1032). In a typical experiment,
direct acylation of excess diamine with di-tert-butyl dicarbonate
(1/3 molar equiv.) in THF is a convenient source of the protected
diamines (PRO-2). BOC-protected carbamate (PRO-A3) may be isolated
by standard procedures well known in the art. The basic carbamates
(PRO-A1) may be obtained by treatment of compound (PRO-A3) with
anhydrous hydrogen chloride in a suitable solvent such as ethyl
acetate.
Example 2
[0348] The following Reaction Scheme 2 illustrates the
intramolecular cyclization-elimination reaction transformation of
an ester derivative prodrug (PRO-A5) to the respective Compound A
and prodrug moiety:
##STR00050##
[0349] Reaction Scheme 2, which is generally applicable to prodrugs
comprising an ester derivative of an ion channel modulating
compound, shows a transformation process that may occur in the
release of an ion channel modulating compound, such as Compound A,
from an ester derivative prodrug, such as formula (PRO-A5). In this
instance, the transformation involves an intramolecular
cyclization-elimination reaction. R' and R'' of prodrug of formula
(PRO-A5) are selected from hydrogen or C.sub.1-C.sub.6-alkyl.
[0350] Synthesis of the prodrug of formula (PRO-A5) above with the
basic ester linker functional group may be carried out according to
a process shown in Reaction Scheme 2A:
##STR00051##
[0351] The process described above in Reaction Scheme 2A is
generally applicable for any ion channel modulating compound
comprising a hydroxyl functionality, although alternate processes
may also be carried out. In general, synthesis of basic esters such
as (PRO-A5) may be prepared by esterification of the free base of a
hydroxyl containing ion channel modulating compound such as
Compound A with an activated N-boc protected dipeptide such as
(PRO-3). Activated dipeptides (PRO-3) are commercially available or
may be prepared by reaction of the corresponding N-boc protected
dipeptide with N,N,N',N'-tetramethyl-O--(N-succinimidyl)uronium
tetrafluoroborate (TSTU), according to the general procedure of
Knorr et al. (see, Knorr, R.; Trzeciak, A.; Bannwarth, W.;
Gillessen, D. Tetrahedron Lett. 1989, 30, 1927). In a typical
experiment, the activated ester may be reacted with molar excesses
of hydroxyl containing ion channel modulating compound, such as
Compound A and triethylamine in a polar solvent such as DMF at
ambient temperature for about 20 h. Standard work-up procedures
well known in the art may be used in the isolation of the
derivatives such as (PRO-A6). Cleavage of the carbamate protecting
group in the presence of ethereal hydrogen chloride provides
prodrugs such as formula (PRO-A5). In one variation, R' and R'' of
a prodrug such as that in formula (PRO-A5) are methyl groups.
Example 3
[0352] The following Reaction Scheme 3 illustrates the cleavage of
an ester bond in an ester derivative prodrug (PRO-A7) to the
respective Compound A and prodrug moiety:
##STR00052##
[0353] Reaction Scheme 3, which is generally applicable to prodrugs
comprising an ester derivative of an ion channel modulating
compound, shows a transformation process that may occur in the
release of an ion channel modulating drug such as Compound A from
an ester derivative prodrug such as that of formula (PRO-A7). In
this instance, the transformation involves an enzymatic cleavage of
the ester bond such as that in (PRO-A7).
[0354] Synthesis of ester derivative prodrugs such as (PRO-A7) may
be carried out by standard procedures well known in the art as
depicted in Reaction Scheme 3A, which is generally applicable to
prodrugs comprising an ester derivative of an ion channel
modulating compound. The process is generally applicable for any
ion channel modulating compound comprising a hydroxyl
functionality, although alternate processes may also be carried
out.
##STR00053##
[0355] In Reaction Scheme 3A, any R group that provides an ester is
suitable in this reaction (see, Bursi, R.; Grootenhuis, A.; van der
Louw, J.; Verhagen, J.; de Gooyer, M.; Jacobs, P.; Leysen, D.,
Steriod 2003, 213-220.). More particular R groups include alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl groups as listed in the "prodrug moieties"
section above. In one variation, the R group is an alkyl or a
substituted alkyl group as listed in the "prodrug moieties" section
above.
[0356] The following examples illustrate the use of prodrug
moieties from the literature that have been reported to have good
pharmacokinetics and safety profiles. Any prodrug moiety may be
used in combination with an ion channel modulating compound to form
a prodrug as described herein, including but not limited to those
described in the "Prodrug Moieties" section above and in the
examples below. The schemes below depicting ion channel modulating
compounds are generally applicable to ion channel modulating
compounds with the same or similar functional groups and the
schemes below depicting prodrugs are generally applicable to
prodrugs with the same or similar linkage bonds and/or prodrug
moieties.
Example 4
[0357] The following Reaction Scheme 4 illustrates the cleavage of
an ester bond in an ester derivative prodrug (PRO-A8) to the
respective Compound A and prodrug moiety:
##STR00054##
[0358] Reaction Scheme 4 shows a transformation process that may
occur in the release of an ion channel modulating compound such as
Compound A from the ester derivative prodrug such as that of
formula (PRO-A8).
[0359] Synthesis of a dimethylglycine ester prodrug such as that of
compound of formula (PRO-A8), i.e.,
(R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate, can be accomplished by standard literature
procedures, as illustrated below in Reaction Scheme 4A. The process
is generally applicable for any ion channel modulating compound
comprising a hydroxyl functionality, although alternate processes
may also be carried out.
##STR00055##
[0360] In general, reaction of Compound A with
4-(dimethylamino)pyridine, N,N-dimethylglycine and
1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride with
N,N-dimethylacetamide may afford the compound (PRO-A8) (see,
Gingrich, D. E.; Reddy, D. R.; Iqbal, M. A.; Singh, J.; Aimone, L.
D.; Angeles, T. S.; Albom, M.; Yang, S.; Ator, M. A.; Meyer, S. L.;
Robinson, C.; Ruggeri, B. A.; Dionne, C. A.; Vaught, J. L.;
Mallamo, J. P.; Hudkins, R. L. J. Med. Chem. 2003, 46,
5375-5388).
[0361] Alternatively, the prodrug of formula (PRO-A8), i.e.,
(R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate, was prepared as follows, as illustrated below
in Reaction Scheme 4B:
##STR00056##
[0362] Specifically, a round bottom flask was charged with the
hydrochloride salt of Compound A (2 g, 5.18 mmol). Air was
evacuated and the system was flushed with nitrogen. Dry
dichloromethane (26 mL) was added through the septum under
nitrogen, and the solution was cooled to 0.degree. C. To the cold
solution was added chloroacetylchloride (1.76 g, 1.24 mL, 15.55
mmol) slowly. The mixture was then stirred at 0.degree. C. for 7 h,
and at ambient temperature overnight (17 h). The reaction was
quenched by adding saturated aqueous sodium bicarbonate. The two
layers were separated and the aqueous layer was extracted with
dichloromethane (4.times.50 mL). The combined organic extracts were
washed successively with water (3.times.50 mL) and brine
(3.times.50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to afford the compound of formula (PRO-A9) (2.20
g, 99.5% yield) as a brown oil. MS (ES.sup.+, MeOH): [M+H].sup.+
426.0.
[0363] To a solution of the compound of formula (PRO-A9) (2.09 g,
4.91 mmol) in dichloromethane (10 mL) was added dimethylamine (2.0
M solution in THF, 1.10 g, 24.49 mmol, 12.24 mL). The solution was
stirred at ambient temperature overnight, then diluted with water
(50 mL) and extracted with dichloromethane (4.times.50 mL). The
combined organic extracts were washed successively with saturated
aqueous NaHCO.sub.3 (3.times.50 mL), water (10.times.50 mL) and
brine (2.times.75 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to afford the compound of formula
(PRO-A8) (1.53 g, 71.6% yield) as a light brown oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 6.75 (m, 3H); 5.14 (m, 1H); 3.85 (s,
3H); 3.83 (s, 3H); 3.73 (m, 1H); 3.55 (m, 1H); 3.30 (br, s, 1H);
3.12 (s, 2H); 2.79 (br, m, 4H); 2.56 (br, s, 1H); 2.32 (m, 7H);
2.19-1.15 (m, 10H); .sup.13C NMR (100 MHz, CDCl.sub.3):
.delta.170.61 (C.dbd.O), 148.77, 147.47, 131.98, 120.79, 112.45,
111.24, 79.47, 74.14, 69.76, 63.86, 60.48, 56.89, 55:95, 55.86,
49.93, 45.63, 45.28, 35.51, 31.32, 28.90, 27.44, 23.34, 22.93; MS
(ES.sup.+, MeOH): [M+H].sup.+435.2, [M+2H].sup.2+ 218.1.
[0364] Alternatively, the prodrug of formula (PRO-A8a), i.e.,
(R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(2-
-aminoethyl)carbamate dihydrochloride, was prepared as follows, as
illustrated below in Reaction Scheme 4C:
##STR00057##
[0365] Specifically, a round bottom flask was charged with
hydrochloride salt of Compound A (2 g, 5.18 mmol). Air was
evacuated and the system was flushed with nitrogen. Dry
dichloromethane (22 mL) was added through the septum under
nitrogen. To this solution was added a solution of
carbonyldiimidazole (1.23 g, 7.75 mmol) in dichloromethane (5 mL)
and the resultant mixture was stirred at ambient temperature
overnight. Ethylenediamine (1.56 g, 1.73 mL, 25.91 mmol) was then
added slowly and stirred for 24 h and then the reaction mixture was
diluted with water (50 mL). The layers were separated and the
aqueous phase was extracted with dichloromethane (4.times.50 mL).
The combined organic extracts were washed successively with
saturated aqueous NaHCO.sub.3 (3.times.50 mL), water (10.times.50
mL) and brine (3.times.50 mL). The organic phase was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated to afford the
compound of formula (PRO-A10a) (1.81 g, 80% yield) as light brown
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.75 (m, 3H); 5.16
(br, s, 1H); 5.05 (m, 1H); 3.85 (s, 3H); 3.83 (s, 3H); 3.73 (m,
1H); 3.55 (m, 1H); 3.29 (m, 1H), 3.19 (m, 2H); 2.79 (m, 6H); 2.50
(m, 1H); 2.32 (m, 1H); 2.09 (m, 1H); 2.02-1.55 (br, m, 8H);
1.40-1.12 (br, m, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
156.64 (C.dbd.O), 148.65, 147.34, 131.91, 120.72, 112.33, 111.09,
79.73, 74.22, 69.68, 63.83, 57.19, 55.89, 55.84/55.80, 49.70,
43.47, 41.65, 36.44/36.32, 31.36, 28.99, 27.52/27.45, 23.42, 23.01;
MS (ES.sup.+, MeOH): [M+H].sup.+436.2, [M+2H].sup.2+ 218.6.
[0366] To a solution of the compound of formula (PRO-A10) (1.81 g,
4.14 mmol) in dichloromethane (10 mL) was added HCl (2.0 M solution
in ether, 14 mL) and stirred at ambient temperature for 15 min. The
solution was then concentrated and the residue was dissolved in
water. The aqueous solution was washed repeatedly with
dichloromethane and the phases were separated. The aqueous phase
was then concentrated and the residue was recrystallized
(i-PrOH/Hexanes) to afford the compound of formula (PRO-A8a), i.e.,
(R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)
cyclohexyl)pyrrolidin-3-yl-2-(2-aminoethyl)carbamate
dihydrochloride, (1.28 g, 60.7% yield) as a light brown oil. MS
(ES.sup.+, MeOH): [M+H].sup.+ 436.2, [M+2H].sup.2+ 218.6.
[0367] In a similar manner as described above, the following
prodrugs of the invention may be prepared: [0368]
(S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate; [0369]
(R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate; [0370]
(S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate; [0371]
(R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate; [0372]
(S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate; [0373]
(R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate; and [0374]
(S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yl-2-(d-
imethylamino)acetate.
Example 5
[0375] The following Reaction Scheme 5 illustrates a transformation
process that may occur in the release of a compound such as a
hydroxy derivative of Compound A from the ester derivative prodrug
such as that of formula (PRO-A-Za1), i.e.,
4-(2-((1R,2R)-2-((R)-3-hydroxypyrrolidin-1-yl)cyclohexyloxy)ethyl)-2-meth-
oxyphenyl 2-(dimethylamino)acetate:
##STR00058##
[0376] Reaction Scheme 5 shows, by way of example but not by way of
limitation, a transformation process that may occur in the release
of a compound such as a hydroxy derivative of Compound A from the
ester derivative prodrug such as that of formula (PRO-A-Za1). In
this instance, the transformation involves an enzymatic cleavage of
the ester bond such as that in (PRO-A-Za1).
[0377] Synthesis of a dimethylglycine ester prodrug such as that of
formula (PRO-A-Za1) above can be accomplished by standard
literature procedures, as illustrated below in Reaction Scheme
5A:
##STR00059##
[0378] The process illustrated above in Reaction Scheme 5A is
generally applicable for any compound comprising a hydroxyl
functionality, although alternate processes may also be carried
out. In a typical experiment, reaction of the hydroxy derivative of
Compound A with 4-(dimethylamino)pyridine, N,N-dimethylglycine and
1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride with
N,N-dimethylacetamide may afford the prodrug of formula
(PRO-A-Za1), i.e.,
4-(2-((1R,2R)-2-(R)-3-hydroxypyrrolidin-1-yl)cyclohexyloxy)ethyl)-2-
-methoxyphenyl 2-(dimethylamino)acetate (see, Gingrich, D. E.;
Reddy, D. R.; Iqbal, M. A.; Singh, J.; Aimone, L. D.; Angeles, T.
S.; Albom, M.; Yang, S.; Ator, M. A.; Meyer, S. L.; Robinson, C.;
Ruggeri, B. A.; Dionne, C. A.; Vaught, J. L.; Mallamo, J. P.;
Hudkins, R. L. J. Med. Chem. 2003, 46, 5375-5388).
Example 6
[0379] The following Reaction Scheme 6 illustrates a shows a
transformation process that may occur in the release of an ion
channel modulating compound such as Compound A from an ester
derivative prodrug such as that of formula (PRO-A11), i.e.,
2-(7-((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid):
##STR00060##
[0380] In this instance, the transformation illustrated above in
Reaction Scheme 6 involves an enzymatic cleavage of the ester bond
in the prodrug of formula (PRO-A11), i.e.,
2-(7-((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid). The
suleptanate group in the prodrug of formula (PRO-A11) is used as a
prodrug in Pharmacia Corp's asthma drug, Promedrol (Paggiaro, P.;
Current Opinion in investigational Drugs. 2000, 1, 97-103). This
ester may be stable in saline solution and may have good
pharmacokinetics and safety profile. The prodrug of formula
(PRO-A11) may be prepared by known procedures, e.g., it can be
prepared either from Compound A via condensation with hemisuberate
or by condensation of Compound A with protected suleptanic acid
(Drug Future. 1997, 22, 833-840. The Synthesis of
Methylprednisolone Suleptenate and a Review of its Biological
Data). Enzymatic cleavage of this group will release the ion
channel modulating agent, Compound A.
[0381] In a similar manner, the following prodrugs of ion channel
modulating compounds may be prepared: [0382]
2-(7-((S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid; [0383]
2-(7-((R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid; [0384]
2-(7-((S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid; [0385]
2-(7-((R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid; [0386]
2-(7-((S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid; [0387]
2-(7-((R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid; and [0388]
2-(7-((S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)-N-methyl-7-oxoheptanamido)ethanesulfonic acid.
Example 7
[0389] A strategy which may be employed in preparing the prodrugs
of the invention is to utilize a water-soluble prodrug moiety with
a self cleavable linker, such as seen with the water solubilizing
prodrug moiety with an ionized amino functionality such as seen in
the following Reaction Scheme 7:
##STR00061##
[0390] The above strategy has been used in the development of
water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727
(Sohma, Y.; Hayashi, Y.; Ito, T.; Matsumoto, H.; Kimura, T.; Kiso,
Y. J. Med. Chem. 2003, 46, 4124-4135).
[0391] Similar strategy can be utilized in the application of
intravenous prodrugs such as those of prodrugs of formula (PRO-A12)
as illustrated below in Reaction Scheme 7A:
##STR00062##
[0392] The ion channel modulating compound may be released by an
intramolecular cyclization-elimination reaction such as the one
depicted in Reaction Scheme 7A. The water solubilizing moiety is
generally a moiety comprising one or more, typically 1 to 6, 2 to
6, 3 to 6, or 1, 2, 3, 4, 5 or 6 or more hydroxyl groups.
Example 8
[0393] The formation of prodrugs of the invention, such as the
prodrugs of formula (PRO-A13) as illustrated below in Reaction
Scheme 8, may be performed by esterification of the free base of a
hydroxyl containing ion channel modulating compound such as
Compound A with an activated peptide such as compound of formula
(PRO-4):
##STR00063##
[0394] Activated peptides are commercially available or may be
prepared by reaction of the corresponding peptide with
N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate
(TSTU), according to the general procedure of Knorr et al. (see,
Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron
Lett. 1989, 30, 1927). In a typical experiment, an activated ester
may be reacted with a molar excess of a hydroxyl containing ion
channel modulating compound such as Compound A and triethylamine in
a polar solvent such as DMF at ambient temperature for 20 h.
Standard work-up procedures well known in the art may permit the
isolation of prodrugs of formula (PRO-A13).
Example 9
[0395] The following Reaction Scheme 9 illustrates transformation
processes that may occur in the release of an ion channel
modulating compound such as Compound A from the ester derivative
prodrug such as that of formula (PRO-A14). In this instance, the
transformation involves an enzymatic cleavage of the ester bond in
the prodrug of formula (PRO-A14):
##STR00064##
[0396] In the above Reaction Scheme 9, the ion channel modulating
compound such as Compound A may be released by spontaneous or
enzymatic hydrolysis of the ester linkage depending on the nature
of this group such as the one depicted in prodrug of formula
(PRO-A14) or the prodrug of formula (PRO-A15). This strategy has
been demonstrated as a promising method of obtaining a prodrug of
the nonsteroidal anti-inflammatory drug (see, NSAID, Rautio, J.;
Nevalainen, T.; Taipale, H.; Vepsalainen.; Gynther, J.; Laine, K.;
Jarvinen, T. J. Med. Chem. 2000, 43, 1489-1494).
[0397] Synthesis of the prodrug of formula (PRO-A14) involves the
formation of a hydroxyl ester derivative such as the prodrug of
formula (PRO-A15) using standard ester bond formation procedures
well known in the art, as illustrated below in Reaction Scheme
9A:
##STR00065##
[0398] As illustrated above in Reaction Scheme 9A, the morpholinyl
(X'=O) and methylpiperazinylacyloxyalkyl (X'=N) prodrugs of formula
(PRO-A14) may be prepared by coupling the corresponding hydroxyl
alkyl ester of the prodrug of formula (PRO-A15) with the
morpholinyl- and (4-methyl-1-piperazinyl)acyl chloride in the
presence of dicyclohexylcarbodiimide (DCC) and
4-(dimethylamino)-pyridine (DMAP) in dry dichloromethane.
Example 10
[0399] Reaction Scheme 10 shows transformation processes that may
occur in the release of an ion channel modulating compound such as
Compound A from a saccharide prodrug such as that of formula
(PRO-A16), i.e.,
6-(2-amino-4-(((2-((((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)methyl)carbamoyloxy)methy-
l)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid)
involving an enzymatic cleavage of the bond in the prodrug of
formula (PRO-A16) where Compound A' is the radical of the following
formula:
##STR00066##
##STR00067##
[0400] In this example, which is generally applicable to like
compounds, the release of the ion channel modulating drug from the
prodrug of formula (PRO-A16) may involve enzymatic hydrolysis of
the prodrug by .beta.-D-glucuronidase as shown above in Reaction
Scheme 10 (see, Bouvier, E.; Thirot, S.; Schmidt, F.; Monneret, C.
Org. Biol. Chem. 2003, 1, 3343-3352).
[0401] The synthesis of the prodrug of formula (PRO-A16) is
illustrated below in Reaction Scheme 10A:
##STR00068##
[0402] As illustrated above in Reaction Scheme 10A, synthesis of a
prodrug of formula (PRO-A16), i.e.,
6-(2-amino-4-(((2-((((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)methyl)carbamoyloxy)methy-
l)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid,
may involve the coupling of a compound such as (PRO-5) with an ion
channel modulating compound such as Compound A under catalytic
basic conditions in dichloromethane to give compound of formula
(PRO-A17). Removal of the TBS protecting groups with hydrogen
fluoride in pyridine followed by palladium may catalyze
hydrogenation of the compound of formula (PRO-A17) to give the
prodrug of formula (PRO-A16) (see, Rautio, J.; Nevalainen, T.;
Taipale, H.; Vepsalainen.; Gynther, J.; Laine, K.; Jarvinen, T. J.
Med. Chem. 2000, 43, 1489-1494). Compound of formula (PRO-5) may be
synthesized according to the method of Florent et al. (Florent,
J-C.; Dong, X.; Gaudel, G.; Mitaku, S.; Monneret, C.; Gesson, J-P.;
Jacquesy, J-C.; Mondon, M.; Renoux, B.; Andrianomenjanahary, S.;
Michel, S.; Koch, M.; Tillequin, F.; Gerken, M.; Czech, J.; Straub,
R.; Bosslet, K. J. Med. Chem. 1998, 41, 3572-3581).
[0403] In a similar manner, the following prodrugs of ion channel
modulating compounds may be prepared: [0404]
6-(2-amino-4-(((2-((((S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyloxy)meth-
yl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid;
[0405]
6-(2-amino-4-(((2-((((R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyloxy)meth-
yl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid;
[0406]
6-(2-amino-4-(((2-((((S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyloxy)meth-
yl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid
[0407]
6-(2-amino-4-(((2-((((R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyloxy)meth-
yl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid;
[0408]
6-(2-amino-4-(((2-((((S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyloxy)meth-
yl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid;
[0409]
6-(2-amino-4-(((2-((((R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl-
)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoyloxy)meth-
yl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid;
and [0410]
6-(2-amino-4-(((2-((((S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyc-
lohexyl)pyrrolidin-3-yloxy)carbonyl)(methyl)amino)ethyl)(methyl)carbamoylo-
xy)methyl)phenoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic
acid.
Example 11
[0411] Another prodrug moiety that may be used in a prodrug of the
invention is a phosphate ester (see, Schultz, C.; Bioorg. Med.
Chem. 2003, 11, 885-898. Egron, D.; Imbach, J-L.; Gosselin, G.;
Aubertin, A-M.; Perigaud, C.; J. Med. Chem. 2003, 46, 4564-4571.
ProQuest Pharmaceutical, INC. PHOS.TM. Prodrugs of Alcohols and
Phenols. 1201 Wakarusa Drive, E2 Lawrence, Kans. 66049). This
functional group is widely used for drugs containing hydroxyl
(--OH) functionalities or amino functionalities, such as hydroxyl
or amino containing ion channel modulating compounds such as
Compound A. In one aspect, a phosphate ester derivative prodrug
such as that of formula (PRO-A19), i.e.,
(1S,3R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium) is provided. In another aspect, a
phosphate ester derivative prodrug such as that of formula
(PRO-A20), i.e,
((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-y-
loxy)methyl dihydrogen phosphate) is provided. Structures of these
two examples are depicted below in FIG. 5. Liberation of the parent
ion channel modulating compound, Compound A, will generally occur
upon enzymatic degradation of the phosphate ester linkage.
##STR00069##
[0412] In a similar manner, the following prodrugs of ion channel
modulating compounds may be prepared: [0413]
(1S,3S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0414]
(1R,3R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0415]
(1R,3S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0416]
(1R,3R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0417]
(1R,3S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0418]
(1S,3R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0419]
(1S,3S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)-3-hydroxy-1-(ph-
osphonooxymethyl)pyrrolidinium; [0420]
((S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate [0421]
((R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate; [0422]
((S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate; [0423]
((R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate; [0424]
((S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate; [0425]
((R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate; and [0426]
((S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)-
methyl dihydrogen phosphate.
Biological Example 1
Assessment of Antiarrhythmic Efficacy
[0427] Antiarrhythmic efficacy may be assessed by investigating the
effect of a compound of the invention on the incidence of cardiac
arrhythmias in anesthetized rats subjected to coronary artery
occlusion. Rats weighing 200-300 gms are subjected to preparative
surgery and assigned to groups in a random block design. In each
case, the animal is anesthetized with pentobarbital during surgical
preparation. The left carotid artery is cannulated for measurement
of mean arterial blood pressure and withdrawal of blood samples.
The left jugular vein is also cannulated for injection of drugs.
The thoracic cavity is opened and a polyethylene occluder loosely
placed around the left anterior descending coronary artery. The
thoracic cavity is then closed. An ECG is recorded by insertion of
electrodes placed along the anatomical axis of the heart. In a
random and double-blind manner, an infusion of vehicle or the
compound to be tested is given about 15 min post-surgery. After 5
minutes infusion, the occluder is pulled so as to produce a
coronary artery occlusion. ECG, arrhythmias, blood pressure, heart
rate and mortality are monitored for 15 minutes after occlusion.
Arrhythmias are recorded as ventricular tachycardia (VT) and
ventricular fibrillation (VF) and scored according to Curtis, M. J.
and Walker, M. J. A., Cardiovasc. Res. 22:656 (1988).
[0428] Rats are excluded from the study if they did not exhibit
pre-occlusion serum potassium concentrations within the range of
2.9-3.9 mM. Occlusion is associated with increases in R-wave height
and "S-T" segment elevation; and an occluded zone (measured after
death by cardiogreen dye perfusion) in the range of 25%-50% of
total left-ventricular weight.
[0429] Results of the test compounds may be expressed as values of
a given infusion rate in micromol/kg/min. (ED.sub.50AA) which will
reduce the arrhythmia score in treated animals to 50% of that shown
by animals treated only with the vehicle in which the test
compound(s) is dissolved.
Biological Example 2
Measurement of Cardiovascular and Behavioral Effects
[0430] Preparative surgery is performed in Sprague Dawley rats
weighing 200-300 gm and anaesthetized with 65 mg/kg (i.p.)
pentobarbital. The femoral artery and vein are cannulated using
polyethylene (PE)-10 tubing. Prior to surgery, this PE-10 tubing
had been annealed to a wider gauge (PE-50) tubing for
externalization. The cannulated PE-10/PE-50 tubing is passed
through a trocar and exteriorised together with three (lead II)
limb ECG leads (see below). The trocar is threaded under the skin
of the back and out through a small incision at the mid-scapular
region. A ground ECG electrode is inserted subcutaneously using a
20 gauge needle with the lead wire threaded through it. To place
the other ECG electrodes, a small incision is made in the anterior
chest region over the heart and ECG leads are inserted into the
subcutaneous muscle layer in the region of the heart using a 20
gauge needle. Other ECG leads are inserted into the subcutaneous
muscle layer in the region near the base of the neck and shoulder
(right side). The animal is returned to a clean recovery-cage with
free access to food and water. The treatment and observational
period for each animal commenced after a 24-hour recovery
period.
[0431] A 15 min observational period is recorded followed by the
intravenous infusion regime of the test compound at an initial dose
of 2.0 .mu.mol/kg/min (at 1 ml/hr). This rate is doubled every 5
minutes until one of the following effects is observed:
[0432] a) partial or complete convulsions
[0433] b) severe arrhythmias
[0434] c) bradycardia below 120 beats/min
[0435] d) hypotension below 50 mmHg
[0436] e) the dose exceeds 32 times the initial starting dose (i.e.
64 .mu.mol/kg/min).
[0437] Blood pressure (BP), heart rate (HR) and ECG variables are
continuously recorded while behavioral responses are also monitored
and the total accumulative drug dose and drug infusion rate at
which the response (such as convulsion, piloerection, ataxia,
restlessness, compulsive chewing, lip-smacking, wet dog shake etc.)
occurred are recorded.
[0438] Estimates of plasma concentrations of the test compound are
determined by removing a 0.5 mL blood sample at the end of the
experiment. Blood samples are centrifuged for 5 min at 4600.times.g
and the plasma decanted. Brain tissue samples are also extracted
and kept frozen (-20.degree. C.) along with the plasma samples for
chemical analysis.
[0439] Electrocardiograph (ECG) parameters: PR, QRS, QT.sub.1 (peak
of T-wave), QT.sub.2 (midpoint of T-wave deflection) and
hemodynamic parameters: BP and HR are analyzed using the automated
analysis function in LabView (National Instruments) with a
customized autoanalysis software (Nortran Pharmaceuticals). The
infused dose producing 25% from control (D.sub.25) for all recorded
ECG variables is determined.
[0440] Results of the tests can be expressed as D.sub.25
(micromol/kg) which are the doses required to produce a 25%
increase in the ECG parameter measured. The increases in P-R
interval and QRS interval indicate cardiac sodium channel blockade
while the increase in Q-T interval indicates cardiac potassium
channel blockade.
Biological Example 3
Electrophysiological Test
In Vivo
[0441] Male Sprague-Dawley rats weighing between 250-350 g are
used. They are randomly selected from a single group and
anesthetized with pentobarbital (65 mg/kg, ip.) with additional
anesthetic given if necessary.
[0442] The trachea is cannulated and the rat is artificially
ventilated at a stroke volume of 10 mL/kg, 60 strokes/minute. The
right external jugular vein and the left carotid artery are
cannulated for intravenous injections of compounds and blood
pressure (BP) recording, respectively.
[0443] Needle electrodes are subcutaneously inserted along the
suspected anatomical axis (right atrium to apex) of the heart for
ECG measurement. The superior electrode is placed at the level of
the right clavicle about 0.5 cm from the midline, while the
inferior electrode is placed on the left side of the thorax, 0.5 cm
from the midline and at the level of the ninth rib.
[0444] Two Teflon-coated silver electrodes are inserted through the
chest wall using 27 G needles as guides and implanted in the
epicardium of left ventricle (4-5 mm apart). Square pulse
stimulation is provided by a stimulator controlled by a computer.
In-house programmed software is used to determine the following:
threshold current (iT) for induction of extra systoles, maximum
following frequency (MFF), effective refractory period (ERP) and
ventricular flutter threshold (VTt). Briefly, iT is measured as the
minimal current (in .mu.A) of a square wave stimulus required to
capture and pace the heart at a frequency of 7.5 Hz and a pulse
width of 0.5 msec; ERP is the minimum delay (in msec) for a second
stimulus required to cause an extra systole with the heart
entrained at a frequency of 7.5 Hz (1.5.times.iT and 0.2 msec pulse
width), MFF is the maximum stimulation frequency (in Hz) at which
the heart is unable to follow stimulation (1.5.times.iT and 0.2
msec pulse width); VTt is the minimum pulse current (in .mu.A) to
evoke a sustained episode of VT (0.2 msec pulse width and 50 Hz)
(Howard, P. G. and Walker, M. J. A., Proc. West. Pharmacol. Soc.
33:123-127 (1990)).
[0445] Blood pressure (BP) and electrocardiographic (ECG)
parameters are recorded and analyzed using LabView (National
Instruments) with a customized autoanalysis software (Nortran
Pharmaceuticals Inc.) to calculate mean BP (mmHg, 2/3 diastolic+1/3
systolic blood pressure), HR (bpm, 60/R-R interval); PR (msec, the
interval from the beginning of the P-wave to the peak of the
R-wave), QRS (msec, the interval from the beginning of the R-wave
due to lack of Q wave in rat ECG, to the peak of the S-wave), QT
(msec, the interval from the beginning of the R-wave to the peak of
the T-wave).
[0446] The initial infusion dose is chosen based on a previous
toxicology study of the test compound in conscious rats. This is an
infusion dose that did not produce a 10% change from pre-drug
levels in haemodynamic or ECG parameters.
[0447] The animal is left to stabilize prior to the infusion
treatment according to a predetermined random and blind table. The
initial infusion treatment is started at a rate of 0.5 mL/hr/300 g
(i.e., 0.5 .mu.mol/kg/min). Each infusion dose is doubled (in rate)
every minutes. All experiments are terminated at 32 mL/hr/300 g
(i.e., 32 .mu.mol/kg/min). Electrical stimulation protocols are
initiated during the last two minutes of each infusion level.
[0448] Responses to test compounds are calculated as percent
changes from pre-infusion values; this normalization is used to
reduce individual variation. The mean values of BP and ECG
parameters at immediately before the electrical stimulation period
(i.e., 3 min post-infusion) are used to construct cumulative
dose-response curves. Data points are fit using lines of best fit
with minimum residual sum of squares (least squares; SlideWrite
program; Advanced Graphics Software, Inc.). D.sub.25's (infused
dose that produced 25% change from pre-infusion value) are
interpolated from individual cumulative dose-response curves and
used as indicators for determining the potency of compounds of the
present invention.
[0449] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification are incorporated herein by reference, in their
entirety.
[0450] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
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