WO2005097869A1 - Polymers comprising ion channel modulating compounds and uses thereof - Google Patents

Polymers comprising ion channel modulating compounds and uses thereof Download PDF

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Publication number
WO2005097869A1
WO2005097869A1 PCT/US2005/011368 US2005011368W WO2005097869A1 WO 2005097869 A1 WO2005097869 A1 WO 2005097869A1 US 2005011368 W US2005011368 W US 2005011368W WO 2005097869 A1 WO2005097869 A1 WO 2005097869A1
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alkyl
hydrogen
crc
polymer
formula
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PCT/US2005/011368
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French (fr)
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Anthony G.M. Barrett
Lewis Siu Leung Choi
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Cardiome Pharma Corp.
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Publication of WO2005097869A1 publication Critical patent/WO2005097869A1/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G61/02—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes
    • C08G61/04—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms
    • C08G61/06—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms prepared by ring-opening of carbocyclic compounds
    • C08G61/08—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms prepared by ring-opening of carbocyclic compounds of carbocyclic compounds containing one or more carbon-to-carbon double bonds in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

Definitions

  • the compounds and methods described herein are generally directed towards polymers comprising ion channel modulating compounds, pharmaceutical compositions and therapeutic uses thereof.
  • the compounds and methods described herein also provide ring opening metathesis polymerization processes for the preparation of polymers comprising ion channel modulating compounds.
  • the field of the compounds and methods described herein is generally ion channel modulating compounds and their uses, and includes but is not limited to 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.
  • AF atrial fibrillation
  • 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.
  • 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.
  • 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).
  • Atrial fibrillation 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).
  • Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia.
  • Class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias.
  • ventricular arrhythmia 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.
  • many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction.
  • Class la, lc 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).
  • 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):5 ⁇ -lQ, 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):5 ⁇ -70, 1998), and they are also associated with a risk of the induction of Torsades de Pointes ventricular tachyarrhythmias.
  • Torsades de Pointes ventricular tachyarrhythmias.
  • the risk of ventricular proarrhythmia is estimated at ⁇ 4.4%, with ⁇ 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).
  • ROM polymers have been reported to be utilized in applications including polymers functionalized, for example, with penicillin (Biagini S.C.G, Gibson V.C., Giles M.R., Marshall E.L, North M. Chem. Commun. 1997, 1097), nucleoside (Gibson V.C., Marshall E.L, North M., Robson D.A., Williams P.J. Chem. Commun. 1997, 1095) or peptides (Biagini S.C.G.
  • One aspect of this invention is directed to polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the ion channel modulating compound is attached to the polymeric backbone via a direct bond or a via a linker moiety.
  • this invention is directed to polymers comprising an ion channel modulating compound, a residual ring opening metathesis polymerization active catalyst trace and a polymeric backbone containing a cycloalkane or a heterocycloalkane moiety.
  • this invention is directed to polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the ion channel modulating compound is selected from a compound of formula (I), a compound of formula (IA), a compound of formula (IX) and Compound A, as described herein.
  • this invention provides polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone comprises a structure of the Formula (PB-1):
  • this invention is directed to polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone is derived from monomer units selected from the group consisting of:
  • R 27 is a heteroatom selected from O, N, S, and P, or R 27 is CH 2 ;
  • z a is an integer from 0 to 10; — indicates a stereochemistry of R or S; and I is an ion channel modulating compound or a linker that is attached to an ion channel modulating compound.
  • 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 combination of cardiac ionic currents.
  • cardiac currents referred to above are the sodium currents and early repolarising currents.
  • Early repolarising currents correspond to those cardiac ionic currents which activate rapidly after depolarization of membrane voltage and which effect repolarisation of the cell.
  • potassium currents may include, but are not limited to, the transient outward current l to ⁇ such as Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current (l K ur) such as Kv1.5, Kv1.4 and Kv2.1).
  • the ultrarapid delayed rectifier current (l Ku r) has also been described as l sus .
  • a second calcium dependent transient outward current (l to2 ) has also been described.
  • 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.
  • arrhythmias such as the various types of atrial and ventricular arrhythmias.
  • arrhythmias such as the various types of atrial and ventricular arrhythmias.
  • arrhythmias such as the various types of atrial and ventricular arrhythmias.
  • the ion channel modulating compounds disclosed in PCT Published Patent Application
  • Alkanoyloxy refers to an ester substituent wherein the ether oxygen is the point of attachment to the molecule.
  • Alkoxy refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH 3 , a d alkoxy].
  • Alkenyloxy refers to an O-atom substituted by an alkenyl group.
  • Alkynyloxy refers to an O-atom substituted by an alkynyl group.
  • Alkoxyalkyl refers to an alkylene group substituted with an alkoxy group.
  • methoxyethyl [CH 3 OCH 2 CH 2 -] and ethoxymethyl (CH 3 CH 2 OCH 2 -] are both C 3 alkoxyalkyI groups.
  • Alkyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, containing no unsaturation and having one point of attachment to the rest of the molecule. Examples include n-propyl (a C 3 alkyl), / ' so-propyl (also a C 3 alkyl), and . " -butyl (a C 4 alkyl).
  • Alkylene refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment. An example is propylene [-CH 2 CH 2 CH 2 -, a C 3 a!kylene].
  • Alkenyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, containing at least one double bond and having one point of attachment to the rest of the molecule.
  • Alkynyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, containing at least one triple bond and having one point of attachment to the rest of the molecule.
  • Alkylcarboxy refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH].
  • 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.
  • Aralkyl refers to an alkylene group wherein one of the points of attachment is to an aryl group.
  • aralkyl group is the benzyl group [C 6 H 5 CH 2 -, a C 7 aralkyl group].
  • Cycloalkyl refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms.
  • An example of a cycloalkyl group is the cyclopentenyl group (C 5 H 7 -), which is a five carbon (C 5 ) unsaturated cycloalkyl group.
  • Carbocyclic refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
  • Carbocyclic aryl refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted. "Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms.
  • 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, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
  • Hydroxyalkyl refers to a branched or unbranched hydrocarbon fragment bearing a hydroxy (-OH) group. Examples include hydroxymethyl (-CH 2 OH, a C ⁇ hydroxyalkyl) and 1 -hydroxyethyl (-CHOHCH 3 , a C 2 hydroxyalkyl).
  • Thioalkyl or “alkylthio” refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH 3 S-, a C ⁇ hioalkyl).
  • 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.
  • a "subject" may generally be any human or non-human animal that would benefit from the methods described in this application.
  • a subject is a human subject.
  • a subject is a warm-blooded animal.
  • a subject is a mammal.
  • the subject is any domestic animal, including, but not limited to dogs and cats.
  • the subject is any livestock animal, including but not limited to horses, pigs and cattle.
  • the subject is any zoo animal, including but not limited to Bengal tigers.
  • 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.
  • prevention 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.
  • 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.
  • 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.
  • inhibiting and similar words such as “inhibit” of any ion channel means any decrease in current through that channel.
  • “inhibition” is used in the context of a specified concentration, it is determined by the IC 50 .
  • an ion channel modulating compound which inhibits an ion channel at a concentration of 1 ⁇ M the ion channel may be said to have an IC 50 of 1 ⁇ M for that ion channel modulating compound.
  • This example is for illustrative purposes only and is in no way intended to be limiting.
  • IC 50 or "IC 50 concentration” means a drug concentration at which the specified current amplitude (peak or steady-state, or integrated current) is inhibited by 50%.
  • blocking or “block” of an ion channel means any block or inhibition of current through that ion channel.
  • 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.
  • “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.
  • “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 ⁇ /, ⁇ /'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N- methylglucamine, procaine, ⁇ /-benzylphenethylamine, 1-para-chloro- benzyl-2- pyrrolidin-V-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
  • compositions described herein 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.
  • 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. 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.
  • the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.
  • 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.
  • the residue is the L form.
  • amino acid refers to ⁇ -amino acids which are racemic, or of either the D- or L-configuration.
  • the designation "d" preceding an amino acid designation refers to the D-isomer of the amino acid.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • conventional techniques such as reverse phase HPLC.
  • the compounds of 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.
  • 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.
  • the polymers of the invention may contain an "aminocycloalkyl ether moiety", i.e., the following moiety:
  • 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.
  • “equivalently inhibits” and “equivalently inhibited” means equally inhibits or equally inhibited.
  • equivalently inhibits means that there is no statistically significant difference in inhibition of currents due to application of an ion channel modulating compound.
  • 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.
  • "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).
  • 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.
  • 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.
  • 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.
  • Atrial repolarizing currents means “has a statistically significant effect on atrial repolarizing current amplitudes.”
  • prolongs atrial refractoriness means “has a statistically significant prolonging effect on atrial refractoriness.”
  • 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.
  • 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.
  • rate-dependent inhibition of an ion channel means that the level of inhibition of the ion channel changes with the frequency of stimulation.
  • QT interval is used as is known in the art; for example, the QT interval as measured from an electrocardiogram.
  • prolongs or “prolong” generally means extends or lengthens as in duration.
  • antiarrhythmic is used as is known in the art; for example, as a compound which prevents or alleviates irregularities in heart rate.
  • induces as used herein, unless the context indicates otherwise, generally means to stimulate the occurrence of.
  • chemically induced or “chemically induces” is used as is known in the art.
  • terminatating or “terminates” generally means to bring to an end or to halt.
  • the polymers of the invention comprise an ion channel modulating compound and polymeric backbone.
  • any compound that modulates ion channel activity may by an ion channel modulating compound.
  • a compound that modulates ion channel activity may be a compound that increases or decreases ion channel activity.
  • An ion channel modulating compound that decreases ion channel activity may be a compound that blocks ion channel activity completely or partially.
  • any compound that either singly or together with one or more additional compounds selectively inhibit certain combination of cardiac ionic currents is an ion channel modulating compound.
  • the cardiac currents may be the sodium currents and early repolarizing 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.
  • 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.
  • 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 (l t0 ) and/or the ultrarapid delay rectifier current (l ⁇ ur )-
  • the cardiac transient outward potassium current (l t0 ) and/or the ultrarapid delay rectifier current (l Kur ) may comprise at least one of the Kv4.2, Kv4.3, Kv2.1 , Kv1.4 and Kv1.5 currents.
  • Ion channel modulating compounds may generally have any pKa, however ion channel modulating compounds typically have pKa values of between 4-9, and may have pKa values that are less than 8, including pKa values between 5-7.5. Methods to determine pKa values are well known in the art (see, e.g., Perrin, "Dissociation Constants of Organic Bases in Aqueous Solution", Butterworth, London, 1972). 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.
  • ion channel modulating compounds have structural characteristics that may be determined by various physical methods, such as single crystal X-ray crystallography.
  • one of J and K comprises a hydrophobic moiety, such as but not limited to a moiety comprising alkyl and/or aryl moieties.
  • one of J and K comprises a hydrophobic aromatic moiety, which may be attached to the cycloalkane ring of structure T via an ether bond.
  • one of J and 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.
  • one of J and K comprises a nitrogen containing moiety substituted with a hydroxyl moiety or the like, such as a pyrrolidinyl moiety.
  • n 2
  • J comprises an aromatic moiety
  • K comprises a nitrogen containing moiety substituted with a hydroxyl moiety or the like.
  • the cycloalkane ring may be optionally substituted.
  • the cycloalkane ring may be replaced by a structural moiety imparting rigidity to the relative positions of the J and K groups.
  • the ion channel modulating compound may be a compound of formula
  • 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.
  • the amino substituted cycloalkane ring is further substituted with an ether moiety.
  • the ion channel modulating compound comprises an aminocyclohexyl ring that is further substituted with an ether moiety.
  • 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,
  • One embodiment of the invention is directed to polymers comprising an ion chann ⁇ l modulating compound and a polymeric backbone wherein the ion channel modulating compound is a compound of formula (I), or solvates or pharmaceutically acceptable salts thereof:
  • Y is selected from a direct bond, O, S and C C alkyIene;
  • R 13 is selected from hydrogen, C ⁇ C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl;
  • R 1 and R 2 are independently selected from hydrogen, C ⁇ -C 8 alkyl, C 3 -C 8 alkoxyalkyl, d-C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or R-i and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (I), form a ring denoted by formula (II):
  • 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, d-C 3 hydroxyalkyl, oxo, C 2 -C acyl, d-C 3 alkyl, C 2 -C 4 alkylcarboxy, d-C 3 alkoxy, d-C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur, and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted
  • R , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C Cealkyl, d-C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, d-C 6 thioalkyl and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl and C Cealkyl;
  • R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, d-C 6 alkyl, d-Cealkoxy, C 2 -C 7 alkoxycarbonyl, d-C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 17 when Z is N, and R 17 is selected from hydrogen, d-C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and
  • polymers wherein the ion channel modulating compound of formula (I) is selected from the group consisting of the following: (1 R,2R)/ (1S,2S)-[2 (4-morpholinyl)- 1-(2-naphthenethoxy)]cyclohexane; (1 R,2R)/ ( ⁇ 1S,2S)-[2 (4-morpholinyl) 1 -(1 -naphthenethoxy)]cyclohexane; (1 R,2R)/ ( ⁇ 1S,2S)-[2 (4-morpholinyl)- 1-(4-bromophenethoxy)]cyclohexane; (1 R,2R)/ ( ⁇ 1S,2S)-[2 (4-morpholinyl) 1-[2-(2-naphthoxy)ethoxy]]cyclohexane; (1 R,2R)/ ⁇ (1S,2S)-[2 (4-morpholinyl) 1-[2-(2-naphthoxy)eth
  • Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone 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:
  • 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:
  • R 7 , R 8 and R 9 are independently selected from hydrogen, hydroxy and C ⁇ -C 6 alkoxy, as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R 7 , R 8 and R 9 cannot all be hydrogen.
  • the ion channel modulating compound of formula (IA) is selected from the group consisting of the following: (1 R,2R)/(1 S,2S)-2-[(3R)/(3S)-hydroxypyrroIidinyl]-1 -(3,4- dimethoxyphenethoxy)-cyclohexane; (1R,2R)/(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2R)/(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2R)-2-[(3R)-
  • Ri and R 2 are independently selected from hydrogen, d-C 8 aIkyl, C 3 - C 8 alkoxyalkyl, d-C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or are independently selected from C 3 -C 8 alkoxyaIkyl, C C 8 hydroxyalkyl, and C 7 -C 12 aralkyl; or R-, and R 2 , are taken together with the nitrogen atom to which they are directly attached in formula (XXVI) to form a ring denoted by formula (II):
  • 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.
  • R 21 and R 22 are independently selected from hydrogen, hydroxyl and d-C 6 alkoxy. In another version of formula (XXVI), both R 21 and R 22 are methoxy.
  • Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone wherein the ion channel modulating compound is a compound of formula (IX), or solvates or pharmaceutically acceptable salts thereof:
  • n is selected from 1 , 3 and 4;
  • Q is either O (oxygen) or -O-C(O);
  • Y is selected from a direct bond, O, S, and C C 4 alkylene;
  • R 13 is selected from hydrogen, CrC 6 alkyl, C 3 -C 8 cycloalkyl, aryl, and benzyl;
  • R T and R 2 are independently selected from hydrogen, d-C 8 alkyl,
  • 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, d-C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C C 3 alkyl, C 2 -C 4 alkylcarboxy, C C 3 alkoxy, d-C 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C C 6 alkyl, d-C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, CrC 6 thioalkyl and N(R ⁇ 5 ,R ⁇ 6 ) where R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl and C C 6 alkyl;
  • R 10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C Cealkyl, CrC 6 alkoxy, C 2 -C 7 alkoxycarbonyl, d-Cethioalkyl, and N(R 5 ,R ⁇ e) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC 6 alkyl;
  • R ⁇ 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, CrC 6 alkyl, CrC 6 alkoxy, C 2 -C 7 alkoxycarbonyl, CrC 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R ⁇ e are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown in formula (IX) when Z is CH or N, or Z may be directly bonded to R 17 when Z is N, and R 17 is selected from hydrogen, d-C 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl
  • VII (VIM) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
  • polymers whereing the ion channel modulating compound of formula (IX) is selected from the group consisting of the following: (1 R,2R)/(1 S,2S)-2-(4-morpholinyl)-1 -(2-naphthalenethoxy)cyclopentane monohydrochloride; and (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -(2,6-dichlorophenethoxy)cyclopentane monohydrochloride.
  • Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone wherein the ion channel modulating compound is Compound A: or pharmaceutically acceptable salts or solvates thereof.
  • Compound A has the chemical name of (1/ * ?, 2R)-2-[(3/ * ?)-hydroxypyrrolidinyl]-1- (3,4-dimethoxyphenethoxy)cyclohexane.
  • 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.
  • the ion channel modulating compound is a protonated version of any of the aminocycloalkyl ether compounds described herein. That is, for each aminocycloalkyl ether compound described herein, the quaternary protonated amine forms of the compound may also be considered as an aminocycloalkyl ether ion -channel modulating compounds. 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.
  • 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.
  • the bonds from the cycloalkyl ring to the 1 -oxygen and 2-nitrogen atoms in the above described compounds may be relatively disposed in either a cis or trans relationship.
  • the stereochemistry of the amine and ether substituents of the cycloalkyl ring is either (R,R)-trans or (S,S)-trans.
  • the stereochemistry is either (R,S)-c/s or (S,R)-c/s.
  • Polymers of the invention comprising a polymeric backbone and an ion channel modulating compound are described herein, wherein the ion channel modulating compound is attached to the polymeric backbone via a direct bond or via a linker.
  • Any ion channel modulating compound may be used in the polymers described herein, including but not limited to those described above, particularly ion channel modulating compounds of formulae (I), (IA), (IX), (XXVI) and Compound A.
  • Any polymer may also be used, and may be made from any monomeric units, in particular ones that give rise to a polymer that contains or can attach an ion channel modulating compound.
  • the ion channel modulating compound to be incorporated into the polymer may increase or decrease ion channel activity.
  • the ion channel modulating compound may be used in the treatment of arrhythmia.
  • the ion channel modulating compound may be used in the treatment of atrial fibrillation.
  • Specific ion channel modulating compounds for use in a polymer are described throughout this patent application.
  • the polymeric backbone is the portion of the polymer with repeating units to which ion channel modulating compounds are attached, either directly or through a linker.
  • the polymeric backbone may be any polymer that is amenable to the " attachment of an ion channel modulating compound and the ion channel modulating compound may be any compound exhibiting ion channel modulating activity.
  • the polymer may comprise more than one type of ion channel modulating compound.
  • An ion channel modulating compound type is determined by the chemical structure, such that ion channel modulating compounds with different chemical structures are of different types.
  • the polymer may contain ion channel modulating compounds in any amount that is allowed by the loading capacity of the polymeric backbone.
  • the loading capacity of the polymeric backbone refers to the number of ion channel modulating compounds that may be attached to the polymeric backbone.
  • the loading capacity is determined by the functional chemistry of the polymeric backbone, and could be determined by one of skill in the art based on knowledge of the polymeric backbone composition.
  • a polymeric backbone that is comprised of "n" monomer units, wherein each monomer unit has only one attachment site for an ion channel modulating compound, will have a loading capacity of "n".
  • a polymer as described herein contains at least one ion channel modulating compound and may contain any number of additional ion channel modulating compounds, up to and including the maximum number that is determined by the loading capacity of the polymeric backbone.
  • the ion channel modulating compounds may be interspersed in the polymeric backbone at any location amenable to their attachment.
  • the ion channel modulating compounds may be attached to the polymeric backbone at each monomer unit in the polymeric backbone, or at fewer than all monomer units.
  • the monomer units with ion channel modulating compounds attached may be present in the polymer in any organizational manner. That is, the polymer may be a heteropolymer comprised of monomer units attached to an ion channel modulating compound ("ICM monomers") and monomer units without an ion channel modulating compound attached (“non-ICM monomers").
  • a heteropolymer of this type may be a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer, or any combination of the foregoing.
  • a heteropolymeric backbone derived from ICM and non-ICM monomer units may have the two monomer units present in any ICM : non-ICM monomer unit ratio.
  • the polymeric backbone is derived from a monomer composition comprising ICM monomers and non-ICM monomers in a 1:1 monomer unit ratio.
  • the polymeric backbone is derived from a monomer composition comprising a first monomer and a second monomer, wherein the first monomer is different than the second monomer and wherein the first monomer is about twice as abundant, by monomer units, than the second monomer.
  • the polymeric backbone is derived from a monomer composition comprising a first monomer and a second monomer, wherein the first monomer is different than the second monomer and wherein the first monomer is more than twice as abundant, by monomer units, than the second monomer.
  • ICM monomers and non-ICM monomers may be present in a polymer in a ratio of ICM monomers : non-ICM monomers of from about 1:1 to about 1 ,000,000:1.
  • the polymer may be any length. As used herein, the length of the polymer refers to the number of monomer units from which the polymeric backbone is derived.
  • the polymeric backbone is derived from "n" monomer units, where n is an integer from 2 to 1 ,000,000.
  • the polymer has a polymeric backbone that is comprised of repeating monomer units.
  • the polymeric backbone may be a homopolymer, wherein all of the monomer units are the same.
  • the polymeric backbone may be a heteropolymer, wherein two or more monomer units are present. If the polymeric backbone is a heteropolymer, the heteropolymer may be a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer, or any combination of the foregoing.
  • the polymeric backbone may be comprised of any two or more of the same monomer units or it may be comprised of any combination of two or more monomer units that are not the same.
  • the polymeric backbone should contain at least one monomer unit that is amenable to the attachment of one or more ion channel modulating compounds.
  • the polymeric backbone may be linear (i.e. derived from linear monomeric units) or it may by cyclic (i.e. derived from a monomer with a cyclic moiety) or may be a combination of linear and cyclic, such as a linear and cyclic block copoiymer.
  • the cyclic moiety may be a cycloalkyl or a heterocycloalkyl group.
  • the heteroatom of a heterocycloalkyi group may be any heteroatom, and in some variations is selected from the group consisting of S, N, O, and P.
  • the polymeric backbone comprises an oxacycloalkyl group.
  • the polymeric backbone may be derived from monomer units by any polymerization process or method, including but not limited to step-growth polymerization (such as condensation), chain growth polymerization (such as free- radical addition polymerization), non-radical addition polymerization, addition polymerization, ring opening metathesis polymerization (ROMP), ring closing metathesis (RCM), polymerizable copolymerization, and other various polymerization methods such as bulk polymerization, gas-phase olefin polymerization, solution polymerization, interfacial polycondensation, suspension polymerization and emulsion polymerization.
  • step-growth polymerization such as condensation
  • chain growth polymerization such as free- radical addition polymerization
  • non-radical addition polymerization addition poly
  • the polymeric backbone is produced by the ROMP of monomer units.
  • the polymeric backbone is produced by the ROMP of cyclic monomer units, such as cyclic monomer units comprising at least one degree of unsaturation, including but not limited to cyclic olefins.
  • the polymeric backbone comprises a cyclic moiety, such as a cycloalkane or heterocycloalkane.
  • the cyclic moiety may be a C 5 -C 8 cycloalkane or a 5 to 8 membered heterocycloalkane ring.
  • the heterocycloalkane may be any heterocycloalkane, including a S, O, N or P containing heterocycloalkane.
  • the polymeric backbone comprises an oxacycloalkane moiety.
  • the polymeric backbone comprises a cyclic structure selected from the group consisting of substituted or unsubstituted: cyclopropane, cyclobutane, cyclopentane, methylcyclopentane, cycloheptane, cyclooctane, 5- acetooxycyclooctane, 5-hydroxycyclooctane, cyclooctane, cyclodecane and cyclododecane.
  • the polymeric backbone comprises a structure of formula (PB-1):
  • n is an integer from 2 to 1 ,000,000; R 27 is a heteroatom selected from O, N, S, and P, or R 27 is CH 2 ; z a is an integer from 0 to 10; — indicates a stereochemistry of R or S; ⁇ m indicates an occupied valency; and 'ww, indicates a bond.
  • the r ⁇ n - ⁇ bond at positions 1 and 2 as shown in Formula (PB-1) are bonds to an ion channel modulating compound or to a linker bond that is in turn bound to an ion channel modulating compound.
  • the polymer backbone comprises the structure of Formula (PB-1), wherein Z a is 0.
  • the polymeric backbone comprises a structure of Formula (PB-1), wherein R 27 is CH 2 .
  • the polymeric backbone comprises a structure of Formula (PB-1), wherein R 27 is CH 2 and z a is 0.
  • the polymeric backbone comprises a structure of Formula (PB-1), wherein R 27 is O.
  • the polymeric backbone comprises a structure of Formula (PB-1), wherein R 27 is O and z a is 0.
  • a polymeric backbone comprising a structure of Formula (PB-1), wherein z a is 0 and n is 3 may be represented by Formula (PB-1 a):
  • valencies indicated by the symbol a m in Formula (PB-1) may be occupied by any organic, inorganic or organometallic moiety.
  • a valency indicated by the symbol - ⁇ TMTM is occupied by an additional monomer unit.
  • the valency indicated by the symbol ⁇ is occupied by a capping group that is derived from a capping agent.
  • R a and R b are any functional group that does not interfere with the polymerization process, such as those listed in the "Monomer Units" section below.
  • a catalyst such as a ROMP active catalyst
  • one of the valencies indicated by the symbol - ⁇ * ⁇ TM in Formula (PB-1) will be occupied by a residual catalyst trace, such as a residual ROMP active catalyst trace.
  • the residual catalyst trace may be from any catalyst that is used in the polymerization reaction of the monomer units, and includes, but is not limited to, the residual catalyst trace that would result from the use of the catalysts detailed in the "catalyst" section below.
  • the residual catalyst trace may be a ruthenium based catalyst trace.
  • the residual catalyst trace is usually present as an alkylidene, such as those that form as an end product of a ROMP reaction between a catalyst and ROMP active monomer units.
  • substituents originating from the catalyst such as substituents originating from a ROMP active catalyst.
  • the substituents may be any substituent that originates from a catalyst, including but not limited to the substituents shown as R 28 and R 29 in the "catalyst" section below.
  • one of the valencies indicated by the symbol ⁇ ⁇ "" jn Formula (PB-1) will be occupied by substituents selected from the group consisting of hydrogen, C 2 -C 20 alkenyl, C 2 -C 20 alkynyi, CrC 20 alkyl, aryl, d-C 20 carboxylate, d-C 20 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, CrC 20 alkylthio, d-C 20 alkylsulfonyl or d-C 20 alkylsulfinyl; each optionally substituted with a d-dalkyl, halogen, d-C 5 alkoxy or with a phenyl group optionally substituted with halogen, d-C 5 alkyl or d-dalkoxy.
  • one of the valencies indicated by the symbol ⁇ " in Formula (PB-1) will be occupied by substituents selected from the group consisting of hydrogen, methyl and phenyl.
  • one of the valencies indicated by the symbol ⁇ is occupied by a residual catalyst trace and the other valency indicated by the symbol " ⁇ ⁇ is occupied by one single bond to a hydrogen and another single bond to a phenyl group.
  • the polymeric backbone may be comprised of any monomer units, including monomer units that are amenable to the attachment of ion channel modulating compounds.
  • the monomer units may be linear (i.e., non-cyclic) monomer units, or cyclic monomer units.
  • the monomer units may have one or more unsaturated bond, such as an alkene, an alkyne or other bond with one or more degrees of unsaturation.
  • the cyclic monomer units are cycloolefins or polycycloolefins, wherein a polycycloolefin is a compound containing a cycloolefin and an additional cyclic moiety, such as a cycloalkane or heterocycloalkane.
  • Cyclic monomer units that may be used to prepare the polymeric backbone include, but are not limited to cyclic monomers selected from the group consisting of norbornene, norbomadiene, cyclopentene, dicyclopentadiene, cycloheptene, cyclo-octene, 7- oxanorbornene, 7-oxanorbornadiene, and cyclododecene.
  • the polymeric backbone is comprised of monomer units that may be polymerized by a ring opening metathesis polymerization (ROMP) reaction, known herein as "ROMP active monomers".
  • ROMP ring opening metathesis polymerization
  • ROMP active monomer Any monomer that can be used in a ROMP reaction to form a polymer is a ROMP active monomer, and may be used to prepare the polymeric backbone described in the section above.
  • ROMP active monomers include cyclic olefins, such as those mentioned above, and for instance, norbomene, 7-oxanorbomene or derivatives thereof, such as 7-oxa- bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid.
  • the monomers used to prepare the polymeric backbone are ROMP active monomers selected from the group consisting of norbomene, substituted norbornene, and any substituted or unsubstituted higher cyclic derivative thereof, so long as the monomer contains at least one norbornene or substituted norbornene moiety.
  • the monomers may be substituted with any functional group that does not interfere with the polymerization process. By interfere, it is meant that the functional group completely inhibits the polymerization process such that no polymer is formed.
  • a substituted monomer will be substituted with a hydrocarbyl, halogenated hydrocarbyl, perhalogenated hydrocarbyl or other functional group.
  • Examples of functional groups that may be present on a substituted monomer include but are not limited to linear and branched CrC 10 alkyl, linear and branched C 2 -C ⁇ 0 alkenyl, linear and branched C 2 -C 10 alkynyl, C 4 -C 12 cycloalkyl, C 4 -C 12 cycloalkenyl, C 6 -C 12 aryl, and C 7 -C 2 aralkyl. If more than one substituent is present on a substituted monomer, the two or more substituents may be taken together to form a d- C 10 alkylidenyl group.
  • Representative alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Representative alkenyl groups include but are not limited to vinyl, allyl, butenyl, and cyclohexenyl.
  • Representative alkynyl groups include but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.
  • Representative cycloalkyl groups include but are not limited to cyclopentyl, cyclohexyl, and cyclooctyl substituents.
  • Representative aryl groups include but are not limited to phenyl, naphthyl, and anthracenyl.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl.
  • Representative alkylidenyl groups include methylidenyl, and ethylidenyl, groups.
  • Perhalohydrocarbyl groups include perhalogenated phenyl and alkyl groups.
  • the halogenated alkyl groups may be linear or branched and have the formula C z X'" 2z+1 wherein X'" can be selected from a halide, such as F, CI, Br or I, and z is selected from an integer of 1 to 10. In one variation, X'" is fluorine.
  • Perfluorinated substituents may include perfluorophenyl, perfluoromethyl, perfluoroethyl, perfluoropropyl, perfluorobutyl, and perfluorohexyl.
  • cycloalkyl, aryl, and aralkyl groups stated above can be further substituted with linear and branched d-C 5 alkyl and haloalkyl groups, aryl groups and cycloalkyl groups.
  • Examples of other functional groups that may be present on a substituted monomer include but are not limited -(CH 2 ) n C(O)OR 26 , -(CH 2 ) n -C(O)OR 26 -(CH 2 ) n -OR 26 , -(CH 2 ) n -OC(O)R 26 , -(CH 2 ) n -C(O)R 26 , -(CH 2 ) n -OC(O)OR 26 , -(CH 2 ) n SiR 26 , -(CH 2 ) n Si(OR 26 ) 3 wherein n independently represents an integer from 0 to 10 and R 26 independently represents hydrogen, linear and branched C Cioalkyl, linear and branched C 2 -C ⁇ 0 alkenyl, linear and branched C 2 -C 10 alkynyl, C 3 -C ⁇ 2 cycloalkyl, C 6 -C 14 aryl, and C 7 -C
  • the monomeric units that may be used to prepare the polymeric backbone typically have one or more sites for attachment of an ion channel modulating compound or a linker that in turn is attached to an ion channel modulating compound (i.e. "attachment sites").
  • attachment sites i.e. "attachment sites”.
  • the following monomer units of formulae (H1), (H2), and (H3) are used to prepare the polymeric backbone:
  • R 27 is a heteroatom selected from O, N, S, and P, or R 27 is CH 2 ;
  • z a is an integer from 0 to 10; — indicates a stereochemistry of R or S; and I is an ion channel modulating compound or a linker that is attached to an ion channel modulating compound.
  • a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein z a is 0.
  • a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R 27 is CH 2 .
  • a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R 27 is CH 2 and z a is 0.
  • a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R 27 is O.
  • a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R 27 is O and z a is 0.
  • Any ion channel modulating compound may be attached to the monomer units, including but not limited to the ion channel modulating compounds described herein. Linkage The ion channel modulating compound may be attached to the polymeric backbone either directly (i.e.
  • the ion channel modulating compound is bound to the monomer unit via a linkage bond, such as an ester, amide, carbamate, urea or boronate linkage. If additional atoms are required to form the linkage bond, a linkage group may be used, wherein the linkage group may be used to facilitate the formation of the linkage bond.
  • the linkage group may be of any size, from a small moiety that is only used to facilitate the formation of the linkage bond to a larger group which is employed as a connector and/or spacer group.
  • linkers may be used as a spacer molecule to create a separation between the ion channel modulating compound and the polymer, and/or to avoid undesired steric interactions. The spatial separation may be desired for modified, enhanced, or optimal function of the polymer.
  • the linkers may also facilitate the preparation or use of the polymer.
  • the 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 polymer.
  • the linker may be cleavable or noncleavable.
  • a cleavable linker comprises a bond that may be cleaved in vivo or ex vivo including but not limited to cleavage via enzymatic, non-enzymatic, or hydrolytic cleavage.
  • An example of a cleavable linker includes a linker that includes an ester bond.
  • a linker functional group will usually be chosen depending on the chemistry of the ion channel modulating compound and the polymeric backbone.
  • the linker molecule 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 polymeric backbone.
  • the functional groups on the reactive termini may be the same or different.
  • Suitable bifunctional linkers include SMBP.
  • a linker molecule may also be multifunctional.
  • the polymer of the invention may comprise additional optional components, such as a cross-linker.
  • a crosslinker When a crosslinker is employed, the polymer is a crosslinked polymer, which may be less soluble in organic or aqueous environments than the corresponding non-crosslinked polymer.
  • Crosslinked polymers can be prepared by copolymerizing the monomer units described in the section "monomer units" above with a cross-linker, such as a multifunctional norbornene-type crosslinking monomer(s).
  • multifunctional norbornene-type crosslinking monomer is meant that the crosslinking monomer contains at least two norbornene-type moieties, each functionality being addition, ROMP, CM, ADMET, RCM, and OM polymerizable in the presence of a catalyst as described in the "catalyst" section below.
  • the functionality comprises one or more linear or acyclic olefins.
  • the crosslinkable monomers include fused multicyclic ring systems and linked multicyclic ring systems.
  • Divinyl benzene, diallyl phthalate, 1 ,4-bis(exo-norbornenyl-5 ⁇ yl)benzene are cross linkers that may be used to form a cross linked polymer with the polymers described herein.
  • Catalysts The monomer units may be polymerized to form the polymeric backbone. In some instances, the polymerization of the monomer units takes place with the aid of a catalyst.
  • a polymeric backbone as described herein may be produced from a ROMP reaction between monomer units as described in the section regarding monomers above and a ROMP active catalyst.
  • ROMP active catalysts are well known in the art, and any catalyst that is capable of forming a polymer by a ROMP reaction is considered a ROMP active catalyst.
  • the ROMP active catalyst is a ruthenium based transition metal catalyst.
  • the ROMP active catalyst is of the formula: wherein: M is Os or Ru; R 33 and R 3 are the same or different and are each independently an anionic ligand; R 3 ⁇ and R 32 are the same or different and are each independently a neutral electron donor ligand; R 28 and R 29 are each independently hydrogen or a substituent selected from the group consisting of CrC 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, d-C 20 carboxylate, d-C 20 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl,
  • each of the R 28 or R 2 g substituent groups is optionally substituted with one or more moieties selected from the group consisting of d-C 5 alkyl, halogen, d-C 5 alkoxy, and phenyl wherein the phenyl group is optionally substititued with halogen, C C 5 alkyl or d-C 5 alkoxy; and wherein any two or more R 33 , R 34 , R 31 , and R 32 catalyst ligands may optionally by taken together to form a chelating multidentate ligand.
  • R 33 and R 34 of the ROMP active catalyst depicted above are independently selected from a functional group selected from the group consisting of halogen, hydrogen, C C 20 alkyl, aryl, CrC 20 alkoxide, aryloxide, C 2 -C 20 alkoxycarbonyl, arylcarboxylate, CrC 20 carboxylate, aryl, d-C 20 alkylsulfonate, d-C 20 alkylthio, CrC 20 alkylsulfonyl, CrC 20 alkylsulfinyl, wherein each functional group is optionally substituted with a halogen, C C 5 alkyl, d-C 5 alkoxy or phenyl wherein the phenyl group is optionally substituted with a halogen, d-C 5 alkyl, or d-C 5 alkoxy group.
  • a functional group selected from the group consisting of halogen, hydrogen, C C 20 alkyl, aryl, CrC
  • R 33 and R 34 of the ROMP active catalyst depicted above are independently selected from the group consisting of CI, CF 3 CO 2 , CH 3 CO 2 , CFH 2 CO 2 , (CH 3 ) 3 CO, (CF 3 ) 2 (CH 3 )CO, (CF 3 )(CH 3 ) 2 CO, PhO, MeO, EtO, tosylate, mesylate or trifluoromethanesulfonate.
  • both R 33 and R 34 are CI.
  • R 31 and R 32 of the ROMP active catalyst depicted above are independently selected from the group consisting a phosphine, sulfonated phosphine, phosphate, phosphinite, phosphonite, arsine, stibine, ether, amine, amide, sulfoxide, carbonyl, nitrosyl, pyridine or thioether.
  • R 31 and R 32 of the ROMP active catalyst depicted above are independently selected from the group consisting of PMe 3 , PCy 3 , PPh 3 , P(p-Tol) 3 , P(o-Tol) 3 , PMePh 2 , PPhMe 2 , P(CF 3 ) 3 , P(p- FC 6 H 4 ) 3 , pyridine, P(p-CF 3 C 6 H 4 ) 3 , (p-F)pyridine, (p-CF 3 )pyridine, P(C 6 H 4 -SO 3 Na) 3 or P(CH 2 C 6 H 4 -SO 3 Na) 3 .
  • both R 31 and R 32 are PCy 3 .
  • the ROMP active catalyst as depicted above is chosen such that both R 33 and R 34 are CI and both R 31 and R 32 are PCy 3 .
  • at least one of R 31 and R 32 of the ROMP active catalyst is an N-heterocyclic carbene ligand.
  • the N-heterocyclic carbene ligand may be selected from the formulae:
  • R35, R36, R37, R38, R39 and R 0 are each independently hydrogen or a substituent selected from the group consisting of d-C 2 o alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, d-C 20 carboxylate, d-C 20 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, d-C 20 alkylthio, d-C 20 alkylsulfonyl and CrC 20 alkylsulfinyl; wherein each of the R 35 , R 36 , R 37 , R 38 , R 39 and R 40 substituent groups is optionally substituted with one or more moieties selected from the group consisting of CrC 10 alkyl, CrC 10 alkoxy, and aryl, wherein the C C 10 alkyl, CrC 10 alky
  • R 28 is hydrogen and R 29 is phenyl.
  • Examples of Polymers of the Invention The following examples and schemes illustrate particular polymers of the invention and polymer components as described above. However, any combination of the polymer components described above may be used in the preparation of the polymers. That is, any polymeric backbone described above may be attached to any ion channel modulating compound described above to form the polymers described herein. The following are illustrative examples of monomer units used to prepare polymers of the invention comprising polymeric backbones and ion channel modulating compounds.
  • a monomer unit used to prepare the polymeric backbone is selected from the group consisting of formulae (XXXIV), (XXXIV-a), (XXXIV-b), (XXXVI), (XXXVI-a), (XXXVI-b), (IXXXX), (IXXXX-a) and (IXXXX-b):
  • Prot is a protected alkyl group
  • Y is selected from a direct bond, O, S and C C 4 alkylene
  • 11 is any linkage bond to the polymeric backbone including, but not limited to ester, amide, carbamate, urea and boronate linkages
  • R 13 is selected from hydrogen, d-C 6 aIkyl, C 3 -C 8 cycloalkyl, aryl and benzyl
  • Ri and R 2 are independently selected from hydrogen, d-C 6 alkyl, C 3 -C 8 alkoxyalkyl, d-C 8 hydroxyalkyl, and C 7 -C 12 aralkyl and R- ⁇ is taken together with Z' to form a linkage bond to the polymeric backbone; or R ⁇ and R 2 are taken together with the nitrogen atom to which they are
  • R ⁇ 0 and R-n are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl. trifluoromethyl, C 2 -C 7 alkanoyloxy, CrC 6 alkyl, CrC 6 alkoxy, C 2 -C 7 alkoxycarbonyl, CrCethioalkyl, and N(R 15 ,R ⁇ 6 ) where R 1 5 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC 6 alkyl;
  • R 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, CrC 6 alkyl, d-C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, CrC 6 thioalkyl, and N(Ri 5 ,R ⁇ e) where R 5 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown when Z is CH or N, or Z may be directly bonded to R ⁇ 7 when Z is N, and R 17 is selected from hydrogen, CrC 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl; (Vl-Z) where
  • the ion channel modulating compound may be attached to the polymer from any site on the ion channel modulating compound that is amenable to such attachment. For instance, a hydroxyl group or an amino group on the ion channel modulating compound may be used to form a linkage bond between the polymeric backbone or a linker attached to the polymeric backbone and the ion channel modulating compound.
  • An ion channel modulating compound may be attached to a monomer unit prior to polymerization of the monomer to form the polymeric backbone. Alternatively, an ion channel modulating compound may be attached to a pre-formed polymer.
  • An ion channel modulating compound may be attached to the polymeric backbone by the substitution of any atom or valency with a bond to the polymeric backbone or to a linker that is in turn bound to the polymeric backbone. That is, the ion channel modulating compound may be attached to the polymeric backbone at any site on the ion channel modulating compound that allows for such attachment.
  • a valency is said to be substituted with a bond, it is meant that any atom or free electrons present in the ion channel modulating compounds may be replaced by a bond to the polymeric backbone or to a linker, such as the substitution of an O-H bond with an O- polymeric backbone bond.
  • An ion channel modulating compound may be attached to a linker or to the polymeric backbone 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.
  • the ion channel modulating compound is attached to the polymeric backbone via a covalent bond.
  • the following are illustrative examples of polymers comprising polymeric backbones and ion channel modulating compounds.
  • the polymer is a polymer of the formulae (PI), (Pl-a) or (Pl-b): (Pi);
  • Y is selected from a direct bond, O, S and d-C alkylene;
  • Z is any linkage to a polymeric backbone including but not limited to ester, amide, carbamate, urea and boronate linkages;
  • R 13 is selected from hydrogen, CrC 6 alkyl, C 3 -C 8 cycloalkyl, aryl and benzyl;
  • Ri and R 2 are independently selected from hydrogen, CrC 6 alkyl, C 3 -C 8 alkoxyalkyl, CrC 8 hydroxyalkyl, and C 7 -C 12 aralkyl and R-, is taken together with Z to form a linkage bond to the polymeric backbone; or Ri and R 2 are independently selected from C 3 -C 8 alkoxyalkyl, CrC 8 hydroxyalkyl, and C -C
  • ring of formula (ll-Z) wherein the ring of formula (ll-Z) 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, d-C 3 hydroxyalkyl, oxo, C 2 -C 4 acyl, C C 3 alkyl, C 2 -C 4 alkylcarboxy, d-C 3 alkoxy, CrC 20 alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C 3 -C 8 carbocyclic ring, and any one or more of the additional nitrogen ring atoms
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, d-C 6 alkyl, d-C 6 alkoxy, C 2 -C 7 alkoxycarbonyI,
  • R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, d-C 6 alkyl, C C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to "X" as shown in formulae (PI), (Pl-a) or (Pl-b) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is selected from hydrogen, CrC 6 alkyl, C 3 -C 8 cyclo
  • Vll-Z (Vl-Z) (Vlll-Z) including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof;
  • R 30 is independently selected from hydrogen; C 2 -C 20 alkenyl, C 2 -C 20 alkynyl,
  • the polymer is a compound of the formula (Pll):
  • m ⁇ mm is a valency that is occupied by a residual ROMP active catalyst trace; or, ⁇ m is a valency that is occupied by a capping group, such as CH 2 or CR a a nRb wherein R a and R b are as defined above; and n is an integer from 2 to 1 ,000,000.
  • the polymer may comprise a compound of the formula (Pill):
  • the polymer is a compound of the formula (PIV):
  • Prot is a protected alkyl group
  • ⁇ is a valency that is occupied by a residual ROMP active catalyst trace
  • ⁇ " ⁇ " is a valency that is occupied by a capping group, such as CH 2 or CR a R b wherein R a and R b are as defined above
  • n is an integer from 2 to 1 ,000,000.
  • the present invention provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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.
  • the present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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.
  • polymers of the invention selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diaste
  • the present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 0.1mg/mL to 100mg/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.
  • polymers of the invention selected from any of the polymers, or a solvate, pharmaceutically acceptable
  • the present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 5mg/mL to 80mg/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.
  • polymers of the invention selected from any of the polymers, or a solvate, pharmaceutically acceptable salt
  • the present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 10mg/mL to 40mg/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.
  • polymers of the invention selected from any of the polymers, or a solvate, pharmaceutically acceptable salt
  • the present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 20mg/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.
  • polymers of the invention selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate
  • the present invention provides compositions which include a polymer 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 polymer 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 polymer 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 polymer of the invention.
  • 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.
  • HPLC High Performance Liquid Chromatography
  • the present invention provides a pharmaceutical or veterinary composition (hereinafter, simply referred to as a pharmaceutical composition) containing a polymer of the present invention, in admixture with a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutical composition containing an effective amount of polymer of the present invention, in association with a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient.
  • 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.
  • 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 polymer in aerosol form may hold a plurality of dosage units.
  • 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 polymers (active ingredients) known for a particularly desirable effect.
  • 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.
  • the pharmaceutical composition includes a polymer 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.
  • the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory 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.
  • 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.
  • 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; sweeten
  • composition 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.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • 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.
  • compositions When intended for oral administration, preferred compositions contain, in addition to the present polymers, one or more of a sweetening agent, thickening agent, preservative (e.g., alkyl p- hydroxybenzoate), dye/colorant and flavor enhancer (flavorant).
  • a sweetening agent e.g., a styrene, a styrene, a styrene, sorbitol, glucose, or other sugar syrups), buffer, stabilizer and isotonic agent
  • a surfactant e.g., alkyl p-hydroxybenzoate
  • preservative e.g., alkyl p-hydroxybenzoate
  • wetting agent e.g., wetting agent
  • dispersing agent e.g., sorbitol, glucose, or other sugar syrups
  • suspending agent e.g., sorbitol, glucose, or other sugar syrups
  • the emulsifying agent may
  • the liquid pharmaceutical compositions of the invention 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.
  • 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
  • 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.
  • a liquid composition intended for either parenteral or oral administration should contain an amount of the inventive polymer such that a suitable dosage will be obtained. Typically, this amount is at least 0.01 % of a polymer 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 polymer.
  • 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 polymer.
  • 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 polymer of from about 0.1 to about 25% w/v (weight per unit volume).
  • 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.
  • 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 polymer is dispersed homogeneously therein by stirring.
  • the composition may include various materials which modify the physical form of a solid or liquid dosage unit.
  • 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.
  • the active ingredients may be encased in a gelatin capsule or cachet.
  • the composition in solid or liquid form may include an agent which binds to the polymer 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.
  • the pharmaceutical composition of the present invention may consist of gaseous dosage units, e.g., it may be in the form of an aerosol.
  • 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 polymers 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.
  • 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.
  • compositions may be prepared by methodology well known in the pharmaceutical art.
  • the polymers of the present invention may be in the form of a solvate in a pharmaceutically acceptable solvent such as water or physiological saline.
  • the polymers 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.
  • a composition intended to be administered by injection can be prepared by combining the polymer 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 polymer so as to facilitate dissolution or homogeneous suspension of the polymer in the aqueous delivery system.
  • Surfactants are desirably present in aqueous compositions of the invention because the polymers according to the present invention may be hydrophobic.
  • 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. 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.
  • dosage forms include, but are not limited to, parenteral dosage form.
  • dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants, and transdermal delivery systems.
  • 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.
  • compositions of the present invention may be carried out in combination with the administration of other agents.
  • an opioid antagonist such as naloxone
  • a polymer of the invention may be co-administered with epinephrine in order to induce local anesthesia.
  • the present invention provides one or more polymers, or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers 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.
  • 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.
  • a variety of cardiac pathological conditions may be treated and/or prevented by the use of one or more polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • These polymers 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.
  • 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 l to ⁇ such as Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current (l Kur ) such as Kv1.5, Kv1.4 and Kv2.1).
  • the ultrarapid delayed rectifier current (l ⁇ ur ) has also been described as l sus .
  • a second calcium dependent transient outward current (l to2 ) has also been described.
  • the pathological conditions that may be treated and/or prevented by the present invention may include, but are not limited to, various cardiovascular diseases.
  • 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, ventricular flutter.
  • arrhythmias such as the various types of atrial and ventricular arrhythmias, e.g. atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter.
  • the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents.
  • the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents under conditions where an "arrhythmogenic substrate" is present in the heart.
  • An "arrhythmogenic substrate” is characterized by a reduction in cardiac action potential duration and/or changes in action potential morphology, premature action potentials, high heart rates and may also include increased variability in the time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes such as these are observed during conditions of myocardial ischaemia or inflammation and those conditions that precede the onset of arrhythmias such as atrial fibrillation.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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.
  • the cardiac early repolarising currents referred to in the present invention comprise the cardiac transient outward potassium current (l ⁇ 0 ) and/or the ultrarapid delayed rectifier current (l KUr )-
  • the cardiac transient outward potassium current (l t0 ) and/or the ultrarapid delayed rectifier current (l ⁇ ur ) referred to in the present invention comprise at least one of the Kv4.2, Kv4.3, Kv2.1 , Kv1.4 and Kv1.5 currents.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above.
  • ion channels such as cardiac potassium channels
  • Ion channels are blocked in vitro or in vivo.
  • 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. Accordingly, polymers 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 polymers of the invention are found to have significant activity in modulating various ion channel activity both in vivo and in vitro.
  • the present invention provides a polymer of the present invention or a composition containing said polymer, 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 polymers, 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.
  • the invention provides a polymer of the present invention, or composition containing said polymer, 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.
  • the above-mentioned early repolarising currents comprise the transient outward potassium current (l t0 or cardiac or l A for neuronal) and/or the ultrarapid delayed rectifier current (l Kur ); and include at least one of the Kv4.2, Kv4.3, Kv2.1, Kvl.3, Kv1.4 and Kv1.5 currents.
  • the present invention provides a polymer of the present invention, or composition containing said polymer, 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.
  • the present invention provides a polymer of the present invention, or composition containing said polymer, 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.
  • the voltage-activated sodium ion channels comprise the Na v 1 , Na v 2 or Na v 3 series and may be present in cardiac, neuronal, skeletal muscle, central nervous and/or peripheral nervous systems (e.g. hH1 Na).
  • 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 polymer of the present invention, or a composition containing a polymer of the present invention is administered to a warmblooded animal in need thereof.
  • 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.
  • 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 polymer of the present invention or a pharmaceutical composition containing said polymer. These methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal.
  • 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 polymer of the present invention or a pharmaceutical composition containing said polymer.
  • 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.
  • 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.
  • 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 a polymer 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 polymer under conditions and for a time sufficient to permit modulation of the activity of the channels by the polymer.
  • 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 polymer exhibits opioid activity where such activity may not be desired.
  • the naloxone may antagonize opioid activity of the administered polymer without adverse interference with the antiarrhythmic " activity.
  • a polymer of the invention may be co-administered with epinephrine in order to induce local anesthesia.
  • a polymer 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 polymers and compositions. 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 polymer 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 polymer 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 polymer 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.
  • a second test involves administration of a polymer 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.
  • effects on electrical refractoriness are assessed by a single extra beat technique.
  • effects on blood pressure, heart rate and the ECG are recorded.
  • sodium channel blockers produce the ECG changes expected from the first test.
  • 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.
  • a third test involves exposing isolated rat hearts to increasing concentrations of a polymer.
  • Ventricular pressures, heart rate, conduction velocity and ECG are recorded in the isolated heart in the presence of varying concentrations of the polymer.
  • the test provides evidence for direct toxic effects on the myocardium. Additionally, selectivity, potency and efficacy of action of a polymer can be ascertained under conditions simulating ischemia. Concentrations found to be effective in this test are expected to be efficacious in the electrophysiological studies.
  • a fourth test is estimation of the antiarrhythmic activity of a polymer against the arrhythmias induced by coronary artery occlusion in anaesthetized rats. It is expected that a good antiarrhythmic polymer will have antiarrhythmic activity at doses which have minimal effects on either the ECG, blood pressure or heart rate under normal conditions.
  • This information coupled with measurements of the ECG allows one to assess whether sodium and/or potassium channel blockade occurs.
  • a polymer is given as a series of increasing bolus doses.
  • possible toxic effects of a polymer on the dog's cardiovascular system is assessed.
  • the effects of a polymer on the ECG and responses to electrical stimulation are also assessed in intact, anesthetized monkeys (Macaca fascicularis).
  • a blood pressure cannula and ECG electrodes are suitably placed in an anesthetized monkey.
  • a stimulating electrode is placed onto the right atria and/or ventricle, together with monophasic action potential electrode.
  • ECG and electrical stimulation response to a polymer reveal the possible presence of sodium and/or potassium channel blockade.
  • the monophasic action potential also reveals whether a polymer widens the action potential, an action expected of a potassium channel blocker.
  • the following test may be performed.
  • a polymer of the present invention is assessed following subcutaneous administration of sufficient (50 ⁇ 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.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., f-butyldimethylsiiyl, f-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include -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.
  • 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. 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.
  • Mass spectra were recorded for El 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, Wi) with UV detection at 200 nm. A C 18 column with 150 x 4.6 mm, 5 ⁇ 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 ⁇ 100 ⁇ g/mL in mobile phase and 20 ⁇ L were injected into the HPLC. Purity was expressed in area%. CE analyses were performed using a P/ACE System MDQ (Beckman Coulter, Fullerton, CA,).
  • Uncoated silica capillaries with 60 (50 to detector) cm length and 75 ⁇ 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°C.
  • Samples ( ⁇ 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.
  • GC analyses were performed on a Hewlett Packard HP 6890 equipped with 30 m x 0.25 mm x 0.25 ⁇ m capillary column HP-35 (crosslinked 35% PH ME siloxane) and a flame-ionization detector.
  • High-boiling solvents (DMF, DMSO) were Sure/SealTM from Aldrich, and tetrahydrofuran (THF) and ethylene glycol dimethyl ether (DME) were distilled from sodium-benzophenone ketyl.
  • Organic extracts were dried with Na 2 SO 4 unless otherwise noted. All moisture sensitive reactions were performed in dried glassware under a nitrogen or argon atmosphere.
  • the following general schemes and examples describe methods may be used for preparing polymers as described herein.
  • reaction steps according to Schemes 1-19 may be used in the preparation of the polymers, or alternate reaction steps may be used. Alternate reaction steps would be readily recognized by one of skill in the art and include the reaction steps described "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", Richard C. Larock, Wiley- VCH: 1999 and in "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure", Jerry March & Michael Smith, John Wiley & Sons Inc: 2001.
  • the polymer or ROMP active catalysts are commercially available or can be prepared by standard known methods as outlined in for example, U.S. Pat. Nos. 5,312,940, 5,342,909, Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev.
  • 7-Oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid may be synthesized by standard methods from the exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride as outlined for example, France M.B, Alty L.T., Earl M.T J. Chem. Ed. 1999, 76, 659.
  • norbornene derivatives may be obtained from Sigma- Aldrich and include examples such as but not limited to c/s-5-norbornene-et7 ⁇ O-2,3- dicarboxylic acid, 5-norbornene-2-carboxylic acid and mono-methylc/s-5-norbomene- et7 ⁇ O-2,3-dicarboxylate.
  • R 1 any suitable functionality capable of conjugation to an aminocyclohexyl ether
  • Prot protected
  • R group Z" functional group that gives rise to a linkage group (Z 1 ) upon reaction with (XXXII)
  • EXAMPLE 1 In Scheme 1, a norbornene derivative (1 equiv) (XXXIII) may be dissolved in a suitable solvent and mono-protected with a suitable protecting group (suitable methods are set forth in, for example, Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1991)).
  • the mono-protected linker (1 equiv) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (1 equiv) (XXXIII) in a standard coupling reaction.
  • the resultant mono-linked aminocyclohexyl ether (XXXIV) may be isolated and purified.
  • syntheses of monomeric adducts (XXXIV-a) and (XXXIV-b) are shown by illustration but not by way of limitation in Schemes 1a and 1b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXIV). SCHEME 1A.
  • a norbornene derivative (1 equiv) (XXXV) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (1 equiv) (XXXIII) in a standard coupling reaction.
  • the resultant monomer adduct (XXXVI) may be isolated and purified.
  • EXAMPLE 4 A vial may be charged with the monomer adduct (XXXIV) and a stirbar and degassed.
  • the monomer adduct (XXXIV) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • To this may be added the solution of the monomer adduct (XXXIV), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene.
  • the reaction mixture becomes viscous within minutes as the monomer adduct (XXXIV) is polymerized.
  • the resultant polymer product (XXXX) may be washed with a suitable solvent, filtered and isolated.
  • syntheses of monomeric adducts (XXXX-a) and (XXXX-b) are shown by illustration but not by way of limitation in Schemes 4a and 4b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXX).
  • EXAMPLE 5 A vial may be charged with the monomer adduct (XXXVI) and a stirbar and degassed.
  • the monomer adduct (XXXV!) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • To this may be added the solution of the monomer adduct (XXXVI), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene.
  • the reaction mixture becomes viscous within minutes as the monomer adduct (XXXVI) is polymerized.
  • the resultant polymer product (XXXXI) may be washed with a suitable solvent, filtered and isolated.
  • syntheses of monomeric adducts (XXXXI-a) and (XXXXI-b) are shown by illustration but not by way of limitation in Schemes 5a and 5b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXXI).
  • EXAMPLE 6 A vial may be charged with the monomer adduct (IXXXX) and a stirbar and degassed.
  • the monomer adduct (IXXXX) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • To this may be added the solution of the monomer adduct (IXXXX), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., K ⁇ bberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene.
  • EXAMPLE 7 In a typical reaction, a norbornene derivative (1 equiv) (XXXX) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (1 equiv) (XXXIII) in a standard coupling reaction. The resultant monomer adduct (XXXXI) may be isolated and purified. Similarly, syntheses of monomeric adducts (XXXXI-a) and (XXXXI-b) are shown by illustration but not by way of limitation in Schemes 7a and 7b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXXI). SCHEME 7A. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXXI-A) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII-A) TO REAGENT (XXXX).
  • EXAMPLE 7C A vial may be charged with the monomer adduct (XXXXI) and a stirbar and degassed.
  • the monomer adduct (XXXXI) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere.
  • a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., K ⁇ bberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy-ethene.
  • the reaction mixture becomes viscous within minutes as the monomer adduct (XXXXI) may be polymerized.
  • the resultant polymer product (XXXXII) may be washed with a suitable solvent, filtered and isolated.
  • syntheses of monomeric adducts (XXXXII-a) and (XXXXII-b) are shown by illustration but not by way of limitation in Schemes 7d and 7e, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXXII).
  • a vial may be charged with the monomer adduct (XXXXVIII) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles.
  • the monomer adduct (XXXXVIIII) may be dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere.
  • a suitable solvent e.g. toluene
  • a vial may be charged with the monomer adduct (XXXXIV) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles.
  • the monomer adduct (XXXXIV) may be dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere.
  • a suitable solvent e.g. toluene
  • a vial is charged with the monomer adduct (XXXXX) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles.
  • the monomer adduct (XXXXX) is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere.
  • a suitable solvent e.g. toluene
  • a vial is charged with the monomer adduct (XXXXXIII) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles.
  • the monomer adduct (XXXXXIII) is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere.
  • a suitable solvent e.g. toluene
  • a vial is charged with the monomer adduct (XXXXXV) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles.
  • the monomer adduct (XXXXXV) is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere.
  • a suitable solvent e.g. toluene
  • the reaction mixture becomes viscous within minutes as the monomer adduct (XXXXXV) is polymerized.
  • the resultant aminocyclohexyl ether linked polymer product (XXXXXVI) is washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated.
  • a suitable solvent e.g. MeOH, THF or a combination of both
  • a vial is charged with the mono-ester-linked 7-oxanorbornene and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles.
  • the mono-ester- linked 7-oxanorbornene is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere.
  • BIOLOGICAL EXAMPLE 1 ASSESSMENT OF ANTIARRHYTHMIC EFFICACY Antiarrhythmic efficacy may be assessed by investigating the effect of a polymer 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.
  • an infusion of vehicle or the polymer to be tested is given about 15 min post-surgery.
  • 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). 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. Results of the test polymers may be expressed as values of a given infusion rate in micromol/kg/min. (ED 5 oAA) 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 polymer(s) is dissolved.
  • VT ventricular tachycardia
  • VF ventricular fibrillation
  • BIOLOGICAL EXAMPLE 2 MEASUREMENT OF CARDIOVASCULAR AND BEHAVIORAL EFFECTS
  • Preparative surgery is performed in Sprague Dawley rats weighing 200-300 gm and anaesthetized with 65mg/kg (i.p.) pentobarbital.
  • the femoral artery and vein are cannulated using polyethylene (PE)-10 tubing.
  • PE polyethylene
  • PE-50 polyethylene
  • 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.
  • 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 guage 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.
  • a 15 min observational period is recorded followed by the intravenous infusion regime of the test polymer at an initial dose of 2.0 ⁇ mol/kg/min (at 1 ml/hr). This rate is doubled every 5 minutes until one of the following effects is observed: a) partial or complete convulsions b) severe arrhythmias c) bradycardia below 120 beats/min d) hypotension below 50mmHg e) the dose exceeds 32 times the initial starting dose (i.e. 64 ⁇ mol/kg/min).
  • 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.
  • Estimates of plasma concentrations of the test polymer 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 x g and the plasma decanted. Brain tissue samples are also extracted and kept frozen (-20°C) along with the plasma samples for chemical analysis.
  • Electrocardiograph (ECG) parameters PR, QRS, QTi (peak of T-wave), QT 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 25 ) for all recorded ECG variables is determined. Results of the tests can be expressed as D 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) Male Sprague-Dawley rats weighing between 250-350g are used. They are randomly selected from a single group and anesthetized with pentobarbital (65mg/kg, ip.) with additional anesthetic given if necessary. The trachea is cannulated and the rat is artificially ventilated at a stroke volume of 10 mlJkg, 60 strokes/minute. The right external jugular vein and the left carotid artery are cannulated for intravenous injections of polymers and blood pressure (BP) recording, respectively.
  • BP blood pressure
  • 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.
  • Two Teflon-coated silver electrodes are inserted through the chest wall using
  • 27G 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).
  • iT threshold current
  • MFF maximum following frequency
  • ERP effective refractory period
  • VTt ventricular flutter threshold
  • iT is measured as the minimal current (in ⁇ 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 0.5msec; 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 x iT and 0.2msec pulse width), MFF is the maximum stimulation frequency (in Hz) at which the heart is unable to follow stimulation (1.5x iT and 0.2msec pulse width); VTt is the minimum pulse current (in ⁇ A) to evoke a sustained episode of VT (0.2msec pulse width and 50 Hz) (Howard, P.G.
  • 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).
  • BP blood pressure
  • ECG electrocardiographic
  • the initial infusion dose is chosen based on a previous toxicology study of the test polymer in conscious rats. This is an infusion dose that did not produce a 10% change from pre-drug levels in haemodynamic or ECG parameters.
  • 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/h/300g (i.e., O. ' 5 ⁇ mol/kg/min). Each infusion dose is doubled (in rate) every 5 minutes. All experiments are terminated at 32 mL/h/300g (i.e., 32 ⁇ mol/kg/min). Electrical stimulation protocols are initiated during the last two minutes of each infusion level.
  • Responses to test polymers 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 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 polymers of the present invention.

Abstract

Polymers comprising a polymeric backbone and an ion channel modulating compound are described. The ion channel modulating compounds may be aminocyclohexyl ether compounds. Pharmaceutical compositions containing the polymers and therapeutic uses thereof are also described. Also provided are ring opening metathesis polymerization processes for the preparation of the polymers including polymers comprising aminocyclohexyl ether ion channel modulating compounds. ROMP polymerization of ROMP active monomers, such as cyclic olefins (e.g. norbornene or 7-oxanorborne or derivatives of, e.g. 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid) that are attached via a linker to ion channel modulating compounds provide for high loading polymeric drug delivery systems.

Description

POLYMERS COMPRISING ION CHANNEL MODULATING COMPOUNDS AND USES THEREOF
FIELD OF THE INVENTION The compounds and methods described herein are generally directed towards polymers comprising ion channel modulating compounds, pharmaceutical compositions and therapeutic uses thereof. The compounds and methods described herein also provide ring opening metathesis polymerization processes for the preparation of polymers comprising ion channel modulating compounds. The field of the compounds and methods described herein is generally ion channel modulating compounds and their uses, and includes but is not limited to 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 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. 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. 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 these 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 adequeate medical aid. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation. 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 CM., 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 O, Perlmutter R.A., Feinstein A.R., Am. J. Cardiol. 65( I6):1112-6, 1990). 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. Class la, lc 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.O, 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):345-7i, 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):5λ-lQ, 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):5λ-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 ~4.4%, with ~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. Functionalized ring opening metathesis (ROM) polymers have been reported to be utilized in applications including polymers functionalized, for example, with penicillin (Biagini S.C.G, Gibson V.C., Giles M.R., Marshall E.L, North M. Chem. Commun. 1997, 1097), nucleoside (Gibson V.C., Marshall E.L, North M., Robson D.A., Williams P.J. Chem. Commun. 1997, 1095) or peptides (Biagini S.C.G. , Coles M.P., Gibson V.C., Giles M.R., Marshall E.L. North M. Polymer 1998, 39, 1007 and Biagini S.C.G., Davies R.G., Gibson V.C., Giles M.R., Marshall E.L., North M., Robson D.A. Chem. Commun. 1999, 235) are of biological interest. 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 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; and U.S. Published Patent Application No. US2005002693.
SUMMARY OF THE INVENTION One aspect of this invention is directed to polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the ion channel modulating compound is attached to the polymeric backbone via a direct bond or a via a linker moiety. In another aspect, this invention is directed to polymers comprising an ion channel modulating compound, a residual ring opening metathesis polymerization active catalyst trace and a polymeric backbone containing a cycloalkane or a heterocycloalkane moiety. In another aspect, this invention is directed to polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the ion channel modulating compound is selected from a compound of formula (I), a compound of formula (IA), a compound of formula (IX) and Compound A, as described herein. In another aspect, this invention provides polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone comprises a structure of the Formula (PB-1):
Figure imgf000005_0001
wherein: n is an integer from 2 to 1 ,000,000; R27 is a heteroatom selected from O, N, S, and P, or R 7 is CH2; za is an integer from 0 to 10; — indicates a stereochemistry of R or S; ■■■« indicates an occupied valency; and ru r indicates a bond. In another aspect, this invention is directed to polymers comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone is derived from monomer units selected from the group consisting of:
Figure imgf000006_0001
(H1) (H2) (H3) wherein: R27 is a heteroatom selected from O, N, S, and P, or R27 is CH2; za is an integer from 0 to 10; — indicates a stereochemistry of R or S; and I is an ion channel modulating compound or a linker that is attached to an ion channel modulating compound. These aspects and others are described in more detail below.
DETAILED DESCRIPTION OF THE INVENTION 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 combination of cardiac ionic currents. More specifically, the cardiac currents referred to above are the sodium currents and early repolarising currents. 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 ltoι such as Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current (lKur) such as Kv1.5, Kv1.4 and Kv2.1). The ultrarapid delayed rectifier current (lKur) has also been described as lsus. A second calcium dependent transient outward current (lto2) has also been described. 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. 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. US2005002693; the disclosures of which are incorporated in full herein by reference in their entireties.
A. Definitions In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated otherwise. Terms not specifically defined herein are understood to have their common meaning. Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example; d-C20alkyl describes an alkyl group, as defined below, having a total of 1 to 20 carbon atoms, and C-ι-C20alkoxy describes an alkoxy group, as defined below, having a total of 1 to 20 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described. "Acyl" refers to branched or unbranched hydrocarbon fragments terminated by a carbonyl -(C=O)- group containing the specified number of carbon atoms. Examples include acetyl [CH3(C=O)-, a C2acyl] and propionyl [CH3CH2(C=O)-, a C3acyl]. "Alkanoyloxy" refers to an ester substituent wherein the ether oxygen is the point of attachment to the molecule. Examples include propanoyloxy [(CH3CH2(C=O)-O-, a C3alkanoyloxy] and ethanoyloxy [CH3(C=O)-O-, a C2alkanoyloxy]. "Alkoxy" refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH3, a d alkoxy]. "Alkenyloxy" refers to an O-atom substituted by an alkenyl group. "Alkynyloxy" refers to an O-atom substituted by an alkynyl group. "Alkoxyalkyl" refers to an alkylene group substituted with an alkoxy group. For example, methoxyethyl [CH3OCH2CH2-] and ethoxymethyl (CH3CH2OCH2-] are both C3alkoxyalkyI groups. "Alkoxycarbonyl" refers to an ester substituent wherein the carbonyl carbon is the point of attachment to the molecule. Examples include ethoxycarbonyl [CH3CH2O(C=O)-, a C3alkoxycarbonyl] and methoxycarbonyl [CH3O(C=O)-, a C2alkoxycarbonyl]. "Alkyl" refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, containing no unsaturation and having one point of attachment to the rest of the molecule. Examples include n-propyl (a C3alkyl), /'so-propyl (also a C3alkyl), and ."-butyl (a C4alkyl). "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 [-CH2CH2CH2-, a C3a!kylene]. "Alkenyl" refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, containing at least one double bond and having one point of attachment to the rest of the molecule. "Alkynyl" refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, containing at least one triple bond and having one point of attachment to the rest of the molecule. "Alkylcarboxy" refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl [HOOC-CH2-, a C2alkylcarboxy] and carboxyethyl [HOOC-CH2CH2-, a C3alkylcarboxy]. "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. "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 [C6H5CH2-, a C7aralkyl group]. "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 (C5H7-), which is a five carbon (C5) unsaturated cycloalkyl group. "Carbocyclic" refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above. "Carbocyclic aryl" refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted. "Heteroatom" refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms. "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, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like. "Hydroxyalkyl" refers to a branched or unbranched hydrocarbon fragment bearing a hydroxy (-OH) group. Examples include hydroxymethyl (-CH2OH, a Cι hydroxyalkyl) and 1 -hydroxyethyl (-CHOHCH3, a C2hydroxyalkyl). "Thioalkyl" or "alkylthio" refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH3S-, a C^hioalkyl). "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. 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. 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. 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. 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. 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 IC50. For example, an ion channel modulating compound which inhibits an ion channel at a concentration of 1 μM, the ion channel may be said to have an IC50 of 1 μM for that ion channel modulating compound. This example is for illustrative purposes only and is in no way intended to be limiting. As used herein, unless the context makes clear otherwise, "IC50" or "IC50 concentration" means a drug concentration at which the specified current amplitude (peak or steady-state, or integrated current) is inhibited by 50%. 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. 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. "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. "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 Λ/,Λ/'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N- methylglucamine, procaine, Λ/-benzylphenethylamine, 1-para-chloro- benzyl-2- pyrrolidin-V-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. 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. 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 α-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. 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. 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. 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. 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. 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 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. 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. The polymers of the invention may contain an "aminocycloalkyl ether moiety", i.e., the following moiety:
Figure imgf000013_0001
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. 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 due to 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. 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. 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. As used herein, "affects atrial repolarizing currents" means "has a statistically significant effect on atrial repolarizing current amplitudes." As used herein, "prolongs atrial refractoriness" means "has a statistically significant prolonging effect on atrial refractoriness." 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. 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. 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. 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. The term "antiarrhythmic" is used as is known in the art; for example, as a compound which prevents or alleviates irregularities in heart rate. The term "induces" as used herein, unless the context indicates otherwise, generally means to stimulate the occurrence of. 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. Ion Channel Modulating Compounds In one aspect of the invention, the polymers of the invention comprise an ion channel modulating compound and polymeric backbone. 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. 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. 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. 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 (lt0) and/or the ultrarapid delay rectifier current (lκur)- The cardiac transient outward potassium current (lt0) and/or the ultrarapid delay rectifier current (lKur) may comprise at least one of the Kv4.2, Kv4.3, Kv2.1 , Kv1.4 and Kv1.5 currents. Ion channel modulating compounds may generally have any pKa, however ion channel modulating compounds typically have pKa values of between 4-9, and may have pKa values that are less than 8, including pKa values between 5-7.5. Methods to determine pKa values are well known in the art (see, e.g., Perrin, "Dissociation Constants of Organic Bases in Aqueous Solution", Butterworth, London, 1972). 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. 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. "C" angle
Figure imgf000017_0001
(T) 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
IV R" K 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. 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. 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. Compounds of Formulae (I), (IA), (IX), (XXVI) and Compound A One embodiment of the invention is directed to polymers comprising an ion channβl modulating compound and a polymeric backbone wherein the ion channel modulating compound is a compound of formula (I), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000018_0001
wherein, independently at each occurrence, X is selected from a direct bond, -C(R6,R14)-Y- and -C(R13)=CH-, with the proviso that when X is a direct bond and A is formula (III), then at least one of R7, R8 and R9 is not hydrogen; Y is selected from a direct bond, O, S and C C alkyIene; R13 is selected from hydrogen, CτC6alkyl, C3-C8cycloalkyl, aryl and benzyl; R1 and R2 are independently selected from hydrogen, Cι-C8alkyl, C3-C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl; or R-i and R2, when taken together with the nitrogen atom to which they are directly attached in formula (I), form a ring denoted by formula (II):
Figure imgf000019_0001
(II) 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, d-C3hydroxyalkyl, oxo, C2-C acyl, d-C3alkyl, C2-C4alkylcarboxy, d-C3alkoxy, d-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur, and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, d-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or R and R2, 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; R3 and R4 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, d-C6alkyl and d-C6alkoxy, and, when both R3 and R are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; R5, R6 and R14 are independently selected from hydrogen, C C6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-Cι3carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):
Figure imgf000020_0001
where R , R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C Cealkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, d-C6thioalkyl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and C Cealkyl;
Figure imgf000020_0002
(IV) (V) where Rio and R-n are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, C C6alkoxy, C2-C7alkoxycarbonyl, d-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl;
Figure imgf000020_0003
(VI) where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, d-Cealkoxy, C2-C7alkoxycarbonyl, d-C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000021_0001
(VII) (VIII) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. Of particular interest are polymers wherein the ion channel modulating compound of formula (I) is selected from the group consisting of the following: (1 R,2R)/ (1S,2S)-[2 (4-morpholinyl)- 1-(2-naphthenethoxy)]cyclohexane; (1 R,2R)/ (ι 1S,2S)-[2 (4-morpholinyl) 1 -(1 -naphthenethoxy)]cyclohexane; (1 R,2R)/ (ι 1S,2S)-[2 (4-morpholinyl)- 1-(4-bromophenethoxy)]cyclohexane; (1 R,2R)/ (ι 1S,2S)-[2 (4-morpholinyl) 1-[2-(2-naphthoxy)ethoxy]]cyclohexane; (1 R,2R)/ι (1S,2S)-[2 (4-morpholinyl) 1-[2-(4-bromophenoxy)ethoxy]]cyclohexane; (1R,2R)/ι (1S,2S)-[2 (4-morpholinyl) 1-(3,4-dimethoxyphenethoxy)]cyclohexane; (1 R,2R)/ (ι 1S,2S)-[2 (1-pyrrolidinyl)-1 (1-naphthenethoxy)]cyclohexane; (1R,2R)/ι (1S,2S)-[2 (4-morpholinyl) 1-(2-(benzo[b]thiophen-3-yl)]cyclohexane; (1 R,2R)/ (ι 1S,2S)-[2 (4-morpholinyl)- 1-(2-(benzo[b]thiophen-4-yl)]cyclohexane; (1R,2R)/ι (1S,2S)-[2 (4-morpholinyl)- 1-(3-bromophenethoxy)]cyclohexane; (1 R,2R)/ (ι 1S,2S)-[2 (4-morpholinyl) 1-(2-bromophenethoxy)]cyclohexane; (1 R,2R)/(1 S,2S)-[2-(4-morpholinyl) 1-(3-(3,4- dimethoxyphenyl)propoxy)]cyclohexane; (1 R,2R)/(1 S,2S)-[2-[bis(2-methoxyethyl)aminyl]-1 -(2- naphthenethoxy)]cyclohexane; (1 R,2R)/(1 S,2S)-2-(4-morpholinyl)-1 -(3,4-dichlorophenethoxy)cyclohexane; (1 R,2R)/(1S,2S)-2-(3-ketopyrrolidinyl)-1-(1-naphthenethoxy)cyclohexane; (1R,2R)/(1S,2S)-2-(1-acetylpiperazinyl)-1-(2-naphthenethoxy)cyclohexane; (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -(2,6-dichlorophenethoxy)cyclohexane (1 R,2R)/(1S,2S)-2-[1,4-dioxa-7-azaspiro[4.4]non-7-yl]-1-(1- naphthenethoxy)cyclohexane; (1 R,2S)/(1S,2R)-2-(4-morpholinyi)-1-[(2- trifluoromethyl)phenethoxy]cyclohexane monohydrochloride; (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -[3-(cyclohexyl)propoxy]cyclohexane monohydrochloride; (1 R,2R)/(1 S,2S)-2-(3-acetoxypyrrolidinyl)-1 -(1 -naphthenethoxy)cyclohexane monohydrochloride; (1 R,2R)/(1S,2S)-2-(4-morpholinyl)-1-[(2,6-dichlorophenyl)methoxy]cyclohexane monohydrochloride; (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -[(2,6- dichlorophenyl)methoxy]cyclohexane monohydrochloride; (1 R,2R)/(1 S,2S)-2-(3-hydroxypyrrolidinyl)-1 -(2,6- dichlorophenethoxy)cyclohexane monohydrochloride; (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -(2,2-diphenylethoxy)cyclohexane monohydrochloride; (1R,2R)/(1S,2S)-2-(3-thiazolidinyl)-1-(2,6-dichlorophenethoxy)cyclohexane monohydrochloride; (1 R,2S)/(1 S,2R)-2-(3-ketopyrrolidinyl)-1 -(1 -naphthenethoxy)cyclohexane monohydrochloride; and (1 R,2R)/(1 S,2S)-2-(3-hydroxypyrrolidinyl)-1 -(3,4- dimethoxyphenethoxy)cyclohexane monohydrochloride. Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone 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:
Figure imgf000022_0001
wherein, R7, R8 and R9 are independently selected from hydrogen, hydroxy and Cι-C6alkoxy, as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R7, R8 and R9 cannot all be hydrogen. Of particular interest are those polymers wherein the ion channel modulating compound of formula (IA) is selected from the group consisting of the following: (1 R,2R)/(1 S,2S)-2-[(3R)/(3S)-hydroxypyrroIidinyl]-1 -(3,4- dimethoxyphenethoxy)-cyclohexane; (1R,2R)/(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2R)/(1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2R)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1R,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane; (1S,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)- cyclohexane; (1S,2R)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane; (1 S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1 -(3,4-dimethoxyphenethoxy)-cyclohexane; (1S,2S)-2-[(3S)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane; and (1 R,2S)/(1S,2R)-2-[(3R)/(3S)-hydroxypyrrolidinyl]-1-(3,4- dimethoxyphenethoxy)-cyclohexane. Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone wherein the ion channel modulating compound is a compound of formula (XXVI), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000023_0001
(XXVI) wherein: Ri and R2 are independently selected from hydrogen, d-C8aIkyl, C3- C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl; or are independently selected from C3-C8alkoxyaIkyl, C C8hydroxyalkyl, and C7-C12aralkyl; or R-, and R2, are taken together with the nitrogen atom to which they are directly attached in formula (XXVI) to form a ring denoted by formula (II):
Figure imgf000024_0001
(il) 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. d- C3hydroxyalkyl, oxo, C2-C acyl, d-C3alkyl, C2-C4alkylcarboxy, d-C3alkoxy, d- C20alkanoyloxy, or may be substituted to form a spiro five- or six membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, C Cealkyl, C2-C4acyl, C2-C hydroxyalkyl and C3- C8alkoxyalkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (XXVI), may form a bicyclic ring system selected from 3- azabicyclo[3.2.2]nonan-3-yl, 2-azabicycio[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3- yl and 3-azabicyclo[3.2.0]heptane-3-yl; R21 and R22 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C C6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, C C6thioalkyl and N(R15,R 6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and C C6alkyl; and — is a bond that provides either an R or an S stereoisomer at the position indicated by the symbol *. In one version of formula (XXVI), R21 and R22 are independently selected from hydrogen, hydroxyl and d-C6 alkoxy. In another version of formula (XXVI), both R21 and R22 are methoxy. Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone wherein the ion channel modulating compound is a compound of formula (IX), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000025_0001
wherein, independently at each occurrence, n is selected from 1 , 3 and 4; Q is either O (oxygen) or -O-C(O); X is selected from a direct bond, -C(R6,Rι )-Y-, and -C(Rι3)=CH-; Y is selected from a direct bond, O, S, and C C4alkylene; R13 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl, and benzyl; RT and R2 are independently selected from hydrogen, d-C8alkyl,
C3-C8alkoxyalkyl, C C8hydroxyalkyl, and C7-C12aralkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (IX), form a ring denoted by formula (II):
Figure imgf000025_0002
(ll) 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, d-C3hydroxyalkyl, oxo, C2-C4acyl, C C3alkyl, C2-C4alkylcarboxy, C C3alkoxy, d-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, CrC6alkyI, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or Ri and R2, 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; R3 and R4 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, d-C6alkyl and d-C6alkoxy, and, when both R3 and R4 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; R5, R6 and R14 are independently selected from hydrogen, d-C6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-d3carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):
Figure imgf000026_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C C6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl and N(Rι5,Rι6) where R15 and Rι6 are independently selected from hydrogen, acetyl, methanesulfonyl and C C6alkyl;
Figure imgf000026_0002
(IV) (V) where R10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C Cealkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, d-Cethioalkyl, and N(R 5,Rιe) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl;
Figure imgf000027_0001
(VI) where Rι2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl, and N(R15,R16) where R15 and Rιe are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl; and Z is selected from CH, CH2, 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 R17 when Z is N, and R17 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000027_0002
(VII) (VIM) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof. Of particular interest are those polymers whereing the ion channel modulating compound of formula (IX) is selected from the group consisting of the following: (1 R,2R)/(1 S,2S)-2-(4-morpholinyl)-1 -(2-naphthalenethoxy)cyclopentane monohydrochloride; and (1 R,2R)/(1 S,2S)-2-(3-ketopyrrolidinyl)-1 -(2,6-dichlorophenethoxy)cyclopentane monohydrochloride. Another embodiment of the invention is directed to polymers comprising an ion channel modulating compound and a polymeric backbone wherein the ion channel modulating compound is Compound A:
Figure imgf000028_0001
or pharmaceutically acceptable salts or solvates thereof. Compound A has the chemical name of (1/*?, 2R)-2-[(3/*?)-hydroxypyrrolidinyl]-1- (3,4-dimethoxyphenethoxy)cyclohexane. 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. The compounds described above are aminocycloalkyl ether compounds. In another embodiment of the invention, the ion channel modulating compound is a protonated version of any of the aminocycloalkyl ether compounds described herein. That is, for each aminocycloalkyl ether compound described herein, the quaternary protonated amine forms of the compound may also be considered as an aminocycloalkyl ether ion -channel modulating compounds. 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. The bonds from the cycloalkyl ring to the 1 -oxygen and 2-nitrogen atoms in the above described compounds may be relatively disposed in either a cis or trans relationship. In one version, the stereochemistry of the amine and ether substituents of the cycloalkyl ring is either (R,R)-trans or (S,S)-trans. In another version, the stereochemistry is either (R,S)-c/s or (S,R)-c/s.
C. Polymers of the Invention Polymers of the invention comprising a polymeric backbone and an ion channel modulating compound are described herein, wherein the ion channel modulating compound is attached to the polymeric backbone via a direct bond or via a linker. Any ion channel modulating compound may be used in the polymers described herein, including but not limited to those described above, particularly ion channel modulating compounds of formulae (I), (IA), (IX), (XXVI) and Compound A. Any polymer may also be used, and may be made from any monomeric units, in particular ones that give rise to a polymer that contains or can attach an ion channel modulating compound. A polymer may contain a residual catalyst trace, or may be capped with a capping agent, such that the residual catalyst trace is replaced with an organic moiety such as =CH2 or =CRaRb, wherein Ra and Rb may be any alkyl, alkenyl, alkynyl or a substituted derivative thereof. Any ion channel modulating compound may be incorporated into the polymer.
The ion channel modulating compound to be incorporated into the polymer may increase or decrease ion channel activity. 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. Specific ion channel modulating compounds for use in a polymer are described throughout this patent application. The polymeric backbone is the portion of the polymer with repeating units to which ion channel modulating compounds are attached, either directly or through a linker. The polymeric backbone may be any polymer that is amenable to the "attachment of an ion channel modulating compound and the ion channel modulating compound may be any compound exhibiting ion channel modulating activity. The polymer may comprise more than one type of ion channel modulating compound. An ion channel modulating compound type is determined by the chemical structure, such that ion channel modulating compounds with different chemical structures are of different types. The polymer may contain ion channel modulating compounds in any amount that is allowed by the loading capacity of the polymeric backbone. The loading capacity of the polymeric backbone refers to the number of ion channel modulating compounds that may be attached to the polymeric backbone. The loading capacity is determined by the functional chemistry of the polymeric backbone, and could be determined by one of skill in the art based on knowledge of the polymeric backbone composition. For instance, a polymeric backbone that is comprised of "n" monomer units, wherein each monomer unit has only one attachment site for an ion channel modulating compound, will have a loading capacity of "n". A polymer as described herein contains at least one ion channel modulating compound and may contain any number of additional ion channel modulating compounds, up to and including the maximum number that is determined by the loading capacity of the polymeric backbone. For a polymer containing more than one ion channel modulating compound, the ion channel modulating compounds may be interspersed in the polymeric backbone at any location amenable to their attachment. The ion channel modulating compounds may be attached to the polymeric backbone at each monomer unit in the polymeric backbone, or at fewer than all monomer units. When fewer than all monomer units in a polymeric backbone have an ion channel modulating compound attached, the monomer units with ion channel modulating compounds attached may be present in the polymer in any organizational manner. That is, the polymer may be a heteropolymer comprised of monomer units attached to an ion channel modulating compound ("ICM monomers") and monomer units without an ion channel modulating compound attached ("non-ICM monomers"). A heteropolymer of this type may be a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer, or any combination of the foregoing. A heteropolymeric backbone derived from ICM and non-ICM monomer units may have the two monomer units present in any ICM : non-ICM monomer unit ratio. When monomers are said to be present in the polymer, at least a portion of the monomers are present in their polymerized state. In some instances, the polymeric backbone is derived from a monomer composition comprising ICM monomers and non-ICM monomers in a 1:1 monomer unit ratio. In other instances, the polymeric backbone is derived from a monomer composition comprising a first monomer and a second monomer, wherein the first monomer is different than the second monomer and wherein the first monomer is about twice as abundant, by monomer units, than the second monomer. In still another instance, the polymeric backbone is derived from a monomer composition comprising a first monomer and a second monomer, wherein the first monomer is different than the second monomer and wherein the first monomer is more than twice as abundant, by monomer units, than the second monomer. In general, ICM monomers and non-ICM monomers may be present in a polymer in a ratio of ICM monomers : non-ICM monomers of from about 1:1 to about 1 ,000,000:1. The polymer may be any length. As used herein, the length of the polymer refers to the number of monomer units from which the polymeric backbone is derived. Typically, the polymeric backbone is derived from "n" monomer units, where n is an integer from 2 to 1 ,000,000. Polymeric Backbones The polymer has a polymeric backbone that is comprised of repeating monomer units. The polymeric backbone may be a homopolymer, wherein all of the monomer units are the same. Alternatively, the polymeric backbone may be a heteropolymer, wherein two or more monomer units are present. If the polymeric backbone is a heteropolymer, the heteropolymer may be a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer, or any combination of the foregoing. The polymeric backbone may be comprised of any two or more of the same monomer units or it may be comprised of any combination of two or more monomer units that are not the same. The polymeric backbone should contain at least one monomer unit that is amenable to the attachment of one or more ion channel modulating compounds. The polymeric backbone may be linear (i.e. derived from linear monomeric units) or it may by cyclic (i.e. derived from a monomer with a cyclic moiety) or may be a combination of linear and cyclic, such as a linear and cyclic block copoiymer. When at least a portion of the polymeric backbone is cyclic, the cyclic moiety may be a cycloalkyl or a heterocycloalkyl group. The heteroatom of a heterocycloalkyi group may be any heteroatom, and in some variations is selected from the group consisting of S, N, O, and P. In certain variations, the polymeric backbone comprises an oxacycloalkyl group. The polymeric backbone may be derived from monomer units by any polymerization process or method, including but not limited to step-growth polymerization (such as condensation), chain growth polymerization (such as free- radical addition polymerization), non-radical addition polymerization, addition polymerization, ring opening metathesis polymerization (ROMP), ring closing metathesis (RCM), polymerizable copolymerization, and other various polymerization methods such as bulk polymerization, gas-phase olefin polymerization, solution polymerization, interfacial polycondensation, suspension polymerization and emulsion polymerization. Numerous polymerization processes are well known in the art and include but are not limited to those described in "Fundamental Principles of Polymeric Materials, 2nd Ed.", Stephen L. Rosen, John Wiley and Sons, Inc., New York: 1993 and "Plastics Materials and Processing, 2nd Ed.", A. Brent Strong, Prentice Hall, New Jersey: 2000, both of which are incorporated herein by reference in their entirety. In one variation, the polymeric backbone is produced by the ROMP of monomer units. In another variation, the polymeric backbone is produced by the ROMP of cyclic monomer units, such as cyclic monomer units comprising at least one degree of unsaturation, including but not limited to cyclic olefins. In one variation, the polymeric backbone comprises a cyclic moiety, such as a cycloalkane or heterocycloalkane. In a particular variation, the cyclic moiety may be a C5-C8 cycloalkane or a 5 to 8 membered heterocycloalkane ring. The heterocycloalkane may be any heterocycloalkane, including a S, O, N or P containing heterocycloalkane. In one variation, the polymeric backbone comprises an oxacycloalkane moiety. Typically, the polymeric backbone comprises a cyclic structure selected from the group consisting of substituted or unsubstituted: cyclopropane, cyclobutane, cyclopentane, methylcyclopentane, cycloheptane, cyclooctane, 5- acetooxycyclooctane, 5-hydroxycyclooctane, cyclooctane, cyclodecane and cyclododecane. In one embodiment of the invention, the polymeric backbone comprises a structure of formula (PB-1):
Figure imgf000032_0001
wherein: n is an integer from 2 to 1 ,000,000; R27 is a heteroatom selected from O, N, S, and P, or R27 is CH2; za is an integer from 0 to 10; — indicates a stereochemistry of R or S; ^ m indicates an occupied valency; and 'ww, indicates a bond. The bond that is indicated by 'WΛTU mav ^Q g sjng|e or a multiple bond, such as a double bond, and may be a bond to a carbon atom or to a non-carbon atom such as a heteroatom. In some instances, the r^ n-~ bond at positions 1 and 2 as shown in Formula (PB-1) are bonds to an ion channel modulating compound or to a linker bond that is in turn bound to an ion channel modulating compound. In another embodiment of the invention, the polymer backbone comprises the structure of Formula (PB-1), wherein Za is 0. In another variation, the polymeric backbone comprises a structure of Formula (PB-1), wherein R27 is CH2. In a particular variation, the polymeric backbone comprises a structure of Formula (PB-1), wherein R27 is CH2 and za is 0. In yet another variation, the polymeric backbone comprises a structure of Formula (PB-1), wherein R27 is O. In another variation, the polymeric backbone comprises a structure of Formula (PB-1), wherein R27 is O and za is 0. A polymeric backbone comprising a structure of Formula (PB-1), wherein za is 0 and n is 3 may be represented by Formula (PB-1 a):
Figure imgf000033_0001
Formula (PB-1 a) The valencies indicated by the symbol a m in Formula (PB-1) may be occupied by any organic, inorganic or organometallic moiety. In some instances, a valency indicated by the symbol -^™™ is occupied by an additional monomer unit. In some instances, the valency indicated by the symbol ^^~ is occupied by a capping group that is derived from a capping agent. In some instances, the capping group is CH2, such that a =CH2 moiety is provided. In other instances, the capping group is of the formula CRaR , wherein Ra and Rb are independently selected from alkyl, alkenyl, alkynyl or a substituted derivative thereof, such that a =CRaRb moiety is provided. In another embodiment of the invention, Ra and Rb are any functional group that does not interfere with the polymerization process, such as those listed in the "Monomer Units" section below. Typically, for polymers prepared by polymerization using a catalyst, such as a ROMP active catalyst, one of the valencies indicated by the symbol -^*^™ in Formula (PB-1) will be occupied by a residual catalyst trace, such as a residual ROMP active catalyst trace. The residual catalyst trace may be from any catalyst that is used in the polymerization reaction of the monomer units, and includes, but is not limited to, the residual catalyst trace that would result from the use of the catalysts detailed in the "catalyst" section below. In a particular variation, the residual catalyst trace may be a ruthenium based catalyst trace. The residual catalyst trace is usually present as an alkylidene, such as those that form as an end product of a ROMP reaction between a catalyst and ROMP active monomer units. Typically, when one of the valencies indicated by the symbol """^ in Formula (PB-1) is occupied by a residual catalyst trace, the other valency indicated by the symbol ^™" will be occupied by substituents originating from the catalyst, such as substituents originating from a ROMP active catalyst. The substituents may be any substituent that originates from a catalyst, including but not limited to the substituents shown as R28 and R29 in the "catalyst" section below. In another embodiment of the invention, one of the valencies indicated by the symbol ■■^"" jn Formula (PB-1) will be occupied by substituents selected from the group consisting of hydrogen, C2-C20alkenyl, C2-C20alkynyi, CrC20alkyl, aryl, d-C20carboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, CrC20alkylthio, d-C20alkylsulfonyl or d-C20alkylsulfinyl; each optionally substituted with a d-dalkyl, halogen, d-C5alkoxy or with a phenyl group optionally substituted with halogen, d-C5alkyl or d-dalkoxy. In one variation, one of the valencies indicated by the symbol ^^" in Formula (PB-1) will be occupied by substituents selected from the group consisting of hydrogen, methyl and phenyl. In yet another variation, one of the valencies indicated by the symbol ■■ββ is occupied by a residual catalyst trace and the other valency indicated by the symbol "■^ is occupied by one single bond to a hydrogen and another single bond to a phenyl group. Monomer Units The polymeric backbone may be comprised of any monomer units, including monomer units that are amenable to the attachment of ion channel modulating compounds. The monomer units may be linear (i.e., non-cyclic) monomer units, or cyclic monomer units. The monomer units may have one or more unsaturated bond, such as an alkene, an alkyne or other bond with one or more degrees of unsaturation. In some instances, the cyclic monomer units are cycloolefins or polycycloolefins, wherein a polycycloolefin is a compound containing a cycloolefin and an additional cyclic moiety, such as a cycloalkane or heterocycloalkane. Cyclic monomer units that may be used to prepare the polymeric backbone include, but are not limited to cyclic monomers selected from the group consisting of norbornene, norbomadiene, cyclopentene, dicyclopentadiene, cycloheptene, cyclo-octene, 7- oxanorbornene, 7-oxanorbornadiene, and cyclododecene. In some instances, the polymeric backbone is comprised of monomer units that may be polymerized by a ring opening metathesis polymerization (ROMP) reaction, known herein as "ROMP active monomers". Any monomer that can be used in a ROMP reaction to form a polymer is a ROMP active monomer, and may be used to prepare the polymeric backbone described in the section above. Examples of ROMP active monomers include cyclic olefins, such as those mentioned above, and for instance, norbomene, 7-oxanorbomene or derivatives thereof, such as 7-oxa- bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid. In one embodiment of the invention, the monomers used to prepare the polymeric backbone are ROMP active monomers selected from the group consisting of norbomene, substituted norbornene, and any substituted or unsubstituted higher cyclic derivative thereof, so long as the monomer contains at least one norbornene or substituted norbornene moiety. In general, the monomers may be substituted with any functional group that does not interfere with the polymerization process. By interfere, it is meant that the functional group completely inhibits the polymerization process such that no polymer is formed. Typically, a substituted monomer will be substituted with a hydrocarbyl, halogenated hydrocarbyl, perhalogenated hydrocarbyl or other functional group. Examples of functional groups that may be present on a substituted monomer include but are not limited to linear and branched CrC10alkyl, linear and branched C2-Cι0alkenyl, linear and branched C2-C10alkynyl, C4-C12cycloalkyl, C4-C12cycloalkenyl, C6-C12aryl, and C7-C2 aralkyl. If more than one substituent is present on a substituted monomer, the two or more substituents may be taken together to form a d- C10alkylidenyl group. Representative alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. Representative alkenyl groups include but are not limited to vinyl, allyl, butenyl, and cyclohexenyl. Representative alkynyl groups include but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl. Representative cycloalkyl groups include but are not limited to cyclopentyl, cyclohexyl, and cyclooctyl substituents. Representative aryl groups include but are not limited to phenyl, naphthyl, and anthracenyl. Representative aralkyl groups include but are not limited to benzyl and phenethyl. Representative alkylidenyl groups include methylidenyl, and ethylidenyl, groups. Perhalohydrocarbyl groups include perhalogenated phenyl and alkyl groups. The halogenated alkyl groups may be linear or branched and have the formula CzX'"2z+1 wherein X'" can be selected from a halide, such as F, CI, Br or I, and z is selected from an integer of 1 to 10. In one variation, X'" is fluorine. Perfluorinated substituents may include perfluorophenyl, perfluoromethyl, perfluoroethyl, perfluoropropyl, perfluorobutyl, and perfluorohexyl. In addition to the halogen substituents, the cycloalkyl, aryl, and aralkyl groups stated above can be further substituted with linear and branched d-C5 alkyl and haloalkyl groups, aryl groups and cycloalkyl groups. Examples of other functional groups that may be present on a substituted monomer include but are not limited -(CH2)nC(O)OR26, -(CH2)n-C(O)OR26-(CH2)n-OR26, -(CH2)n-OC(O)R26, -(CH2)n-C(O)R26, -(CH2)n-OC(O)OR26, -(CH2)nSiR26, -(CH2)nSi(OR26)3 wherein n independently represents an integer from 0 to 10 and R26 independently represents hydrogen, linear and branched C Cioalkyl, linear and branched C2-Cι0alkenyl, linear and branched C2-C10alkynyl, C3-Cι2cycloalkyl, C6-C14aryl, and C7-C24aralkyl. The monomeric units that may be used to prepare the polymeric backbone typically have one or more sites for attachment of an ion channel modulating compound or a linker that in turn is attached to an ion channel modulating compound (i.e. "attachment sites"). In one embodiment of the invention, the following monomer units of formulae (H1), (H2), and (H3) are used to prepare the polymeric backbone:
Figure imgf000036_0001
(H1) (H2) (H3) wherein: R27 is a heteroatom selected from O, N, S, and P, or R27 is CH2; za is an integer from 0 to 10; — indicates a stereochemistry of R or S; and I is an ion channel modulating compound or a linker that is attached to an ion channel modulating compound. In one embodiment, a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein za is 0. In a particular variation, a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R27 is CH2. In another variation, a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R27 is CH2and za is 0. In another variation, a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R27 is O. In another variation, a monomer unit of formula (H1), (H2) or (H3) is used to prepare the polymeric backbone, wherein R27 is O and za is 0. Any ion channel modulating compound may be attached to the monomer units, including but not limited to the ion channel modulating compounds described herein. Linkage The ion channel modulating compound may be attached to the polymeric backbone either directly (i.e. by a direct bond) to the monomer unit from which the polymer backbone is comprised, or via a linkage group. Typically, the ion channel modulating compound is bound to the monomer unit via a linkage bond, such as an ester, amide, carbamate, urea or boronate linkage. If additional atoms are required to form the linkage bond, a linkage group may be used, wherein the linkage group may be used to facilitate the formation of the linkage bond. The linkage group may be of any size, from a small moiety that is only used to facilitate the formation of the linkage bond to a larger group which is employed as a connector and/or spacer group. These groups are collectively referred to as "linkers." The linkers may be used as a spacer molecule to create a separation between the ion channel modulating compound and the polymer, and/or to avoid undesired steric interactions. The spatial separation may be desired for modified, enhanced, or optimal function of the polymer. The linkers may also facilitate the preparation or use of the polymer. The 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 polymer. The linker may be cleavable or noncleavable. A cleavable linker comprises a bond that may be cleaved in vivo or ex vivo including but not limited to cleavage via enzymatic, non-enzymatic, or hydrolytic cleavage. An example of a cleavable linker includes a linker that includes an ester bond. In synthesizing a polymer comprising a linker, it may be useful to employ a linker that has at least two functional groups, one for bonding of the linker to the ion channel modulating compound and one for bonding of the linker to the polymeric backbone. A linker functional group will usually be chosen depending on the chemistry of the ion channel modulating compound and the polymeric backbone. In one variation, the linker molecule 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 polymeric backbone. The functional groups on the reactive termini may be the same or different. Suitable bifunctional linkers include SMBP. A linker molecule may also be multifunctional.
Optional Components of the Polymer The polymer of the invention may comprise additional optional components, such as a cross-linker. When a crosslinker is employed, the polymer is a crosslinked polymer, which may be less soluble in organic or aqueous environments than the corresponding non-crosslinked polymer. Crosslinked polymers can be prepared by copolymerizing the monomer units described in the section "monomer units" above with a cross-linker, such as a multifunctional norbornene-type crosslinking monomer(s). By multifunctional norbornene-type crosslinking monomer is meant that the crosslinking monomer contains at least two norbornene-type moieties, each functionality being addition, ROMP, CM, ADMET, RCM, and OM polymerizable in the presence of a catalyst as described in the "catalyst" section below. In the case of CM, ADMET and RCM reactions, the functionality comprises one or more linear or acyclic olefins. The crosslinkable monomers include fused multicyclic ring systems and linked multicyclic ring systems. Divinyl benzene, diallyl phthalate, 1 ,4-bis(exo-norbornenyl-5~ yl)benzene are cross linkers that may be used to form a cross linked polymer with the polymers described herein. Catalysts The monomer units may be polymerized to form the polymeric backbone. In some instances, the polymerization of the monomer units takes place with the aid of a catalyst. In particular, a polymeric backbone as described herein may be produced from a ROMP reaction between monomer units as described in the section regarding monomers above and a ROMP active catalyst. ROMP active catalysts are well known in the art, and any catalyst that is capable of forming a polymer by a ROMP reaction is considered a ROMP active catalyst. Typically, the ROMP active catalyst is a ruthenium based transition metal catalyst. In one embodiment of the invention, the ROMP active catalyst is of the formula:
Figure imgf000039_0001
wherein: M is Os or Ru; R33 and R3 are the same or different and are each independently an anionic ligand; R3ι and R32 are the same or different and are each independently a neutral electron donor ligand; R28 and R29 are each independently hydrogen or a substituent selected from the group consisting of CrC20alkyl, C2-C20alkenyl, C2-C20alkynyl, aryl, d-C20carboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl,
CrC20alkylthio, CrC20alkylsulfonyl and CrC20alkylsulfinyl, wherein each of the R28 or R2g substituent groups is optionally substituted with one or more moieties selected from the group consisting of d-C5alkyl, halogen, d-C5alkoxy, and phenyl wherein the phenyl group is optionally substititued with halogen, C C5alkyl or d-C5alkoxy; and wherein any two or more R33, R34, R31, and R32 catalyst ligands may optionally by taken together to form a chelating multidentate ligand. In another embodiment, R33 and R34of the ROMP active catalyst depicted above are independently selected from a functional group selected from the group consisting of halogen, hydrogen, C C20alkyl, aryl, CrC20alkoxide, aryloxide, C2-C20alkoxycarbonyl, arylcarboxylate, CrC20carboxylate, aryl, d-C20alkylsulfonate, d-C20alkylthio, CrC20alkylsulfonyl, CrC20alkylsulfinyl, wherein each functional group is optionally substituted with a halogen, C C5alkyl, d-C5alkoxy or phenyl wherein the phenyl group is optionally substituted with a halogen, d-C5alkyl, or d-C5alkoxy group. In another embodiment, R33 and R34 of the ROMP active catalyst depicted above are independently selected from the group consisting of CI, CF3CO2, CH3CO2, CFH2CO2, (CH3)3CO, (CF3)2(CH3)CO, (CF3)(CH3)2CO, PhO, MeO, EtO, tosylate, mesylate or trifluoromethanesulfonate. Typically, both R33 and R34 are CI. In one embodiment, R31 and R32 of the ROMP active catalyst depicted above, are independently selected from the group consisting a phosphine, sulfonated phosphine, phosphate, phosphinite, phosphonite, arsine, stibine, ether, amine, amide, sulfoxide, carbonyl, nitrosyl, pyridine or thioether. In another variation, R31 and R32 of the ROMP active catalyst depicted above are independently selected from the group consisting of PMe3, PCy3, PPh3, P(p-Tol)3, P(o-Tol)3, PMePh2, PPhMe2, P(CF3)3, P(p- FC6H4)3, pyridine, P(p-CF3C6H4)3, (p-F)pyridine, (p-CF3)pyridine, P(C6H4-SO3Na)3 or P(CH2C6H4-SO3Na)3. Typically, both R31 and R32 are PCy3. In some embodiments, the ROMP active catalyst as depicted above is chosen such that both R33 and R34 are CI and both R31 and R32 are PCy3. In other embodiments, at least one of R31 and R32 of the ROMP active catalyst is an N-heterocyclic carbene ligand. The N-heterocyclic carbene ligand may be selected from the formulae:
Figure imgf000040_0001
wherein: R35, R36, R37, R38, R39 and R 0 are each independently hydrogen or a substituent selected from the group consisting of d-C2o alkyl, C2-C20 alkenyl, C2-C20alkynyl, aryl, d-C20carboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, d-C20alkylthio, d-C20alkylsulfonyl and CrC20alkylsulfinyl; wherein each of the R35, R36, R37, R38, R39 and R40 substituent groups is optionally substituted with one or more moieties selected from the group consisting of CrC10alkyl, CrC10alkoxy, and aryl, wherein the C C10alkyl, CrC10alkoxy, and aryl moieties are optionally substituted with one or more groups selected from a halogen, a d-C5alkyl, d-C5alkoxy, and phenyl. In some embodiments, R28 is hydrogen and R29 is phenyl. Examples of Polymers of the Invention The following examples and schemes illustrate particular polymers of the invention and polymer components as described above. However, any combination of the polymer components described above may be used in the preparation of the polymers. That is, any polymeric backbone described above may be attached to any ion channel modulating compound described above to form the polymers described herein. The following are illustrative examples of monomer units used to prepare polymers of the invention comprising polymeric backbones and ion channel modulating compounds. In one embodiment, a monomer unit used to prepare the polymeric backbone is selected from the group consisting of formulae (XXXIV), (XXXIV-a), (XXXIV-b), (XXXVI), (XXXVI-a), (XXXVI-b), (IXXXX), (IXXXX-a) and (IXXXX-b):
Figure imgf000041_0001
(XXXIV)
Figure imgf000041_0002
(XXXVI)
Figure imgf000042_0001
(XXXVI-b)
Figure imgf000042_0002
Figure imgf000043_0001
(IXXXX-a)
Figure imgf000043_0002
wherein: Prot is a protected alkyl group; X is selected from a direct bond, -C(R6,Rι )-Y- and -C(Rι3)=CH-; Y is selected from a direct bond, O, S and C C4alkylene; 11 is any linkage bond to the polymeric backbone including, but not limited to ester, amide, carbamate, urea and boronate linkages; R13 is selected from hydrogen, d-C6aIkyl, C3-C8cycloalkyl, aryl and benzyl; Ri and R2 are independently selected from hydrogen, d-C6alkyl, C3-C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl and R-\ is taken together with Z' to form a linkage bond to the polymeric backbone; or R\ and R2 are taken together with the nitrogen atom to which they are directly attached to form a ring denoted by formula (ll-Z):
Figure imgf000044_0001
(ll-Z) wherein the ring of formula (ll-Z) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently selected from carbon, nitrogen, oxygen, and sulfur; where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C C3hydroxyalkyl, oxo, C2-C4acyl, d-C3alkyl, C2-C4alkylcarboxy, CrC3alkoxy, CrC20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, d-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or R-i and R2 are taken together with the nitrogen atom to which they are directly attached in formulae (XXXIV), (XXXIV-a), (XXXIV-b), (XXXVI), (XXXVI-a), (XXXVI-b), (IXXXX), (IXXXX-a) and (IXXXX-b) to form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl,
3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl, wherein the bicyclic ring is substituted with Z'; R3 and R4 are independently attached to the cyclohexane ring shown in formulae (XXXIV), (XXXIV-a), (XXXIV-b), (XXXVI), (XXXVI-a), (XXXVI-b), (IXXXX), (IXXXX-a) and (IXXXX-b) at the 3-, 4-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, d-C6alkyl and CrC6alkoxy, and, when both R3 and R are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; R5, R6 and R 4 are independently selected from hydrogen, CrC6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-C 3carbocyclic ring, and ring systems selected from formulae (lll-Z), (IV-Z), (V-Z), (Vl-Z), (Vll-Z) and (Vlll-Z):
Figure imgf000045_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl, aryl and N(R15,Rιe) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6alkyl;
Figure imgf000045_0002
(IV-Z) (V-Z) where Rι0 and R-n are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl. trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,Rι6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl;
Figure imgf000045_0003
(Vl-Z) where R 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl, and N(Ri5,Rιe) where R 5 and Rι6 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown when Z is CH or N, or Z may be directly bonded to Rι7 when Z is N, and R17 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000046_0001
(Vll-Z) (VI ll-Z) including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; and R27 is independently selected from -CH2- or oxygen. The ion channel modulating compound may be attached to the polymer from any site on the ion channel modulating compound that is amenable to such attachment. For instance, a hydroxyl group or an amino group on the ion channel modulating compound may be used to form a linkage bond between the polymeric backbone or a linker attached to the polymeric backbone and the ion channel modulating compound. An ion channel modulating compound may be attached to a monomer unit prior to polymerization of the monomer to form the polymeric backbone. Alternatively, an ion channel modulating compound may be attached to a pre-formed polymer. An ion channel modulating compound may be attached to the polymeric backbone by the substitution of any atom or valency with a bond to the polymeric backbone or to a linker that is in turn bound to the polymeric backbone. That is, the ion channel modulating compound may be attached to the polymeric backbone at any site on the ion channel modulating compound that allows for such attachment. When a valency is said to be substituted with a bond, it is meant that any atom or free electrons present in the ion channel modulating compounds may be replaced by a bond to the polymeric backbone or to a linker, such as the substitution of an O-H bond with an O- polymeric backbone bond. An ion channel modulating compound may be attached to a linker or to the polymeric backbone 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 polymeric backbone via a covalent bond. The following are illustrative examples of polymers comprising polymeric backbones and ion channel modulating compounds. In one embodiment of the invention, the polymer is a polymer of the formulae (PI), (Pl-a) or (Pl-b):
Figure imgf000047_0001
(Pi);
Figure imgf000047_0002
(Pl-a); or
Figure imgf000048_0001
(Pl-b) wherein: X is selected from a direct bond, -C(R6,Rι4)-Y- and -C(Rι3)=CH-; Y is selected from a direct bond, O, S and d-C alkylene; Z is any linkage to a polymeric backbone including but not limited to ester, amide, carbamate, urea and boronate linkages; R13 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl; Ri and R2 are independently selected from hydrogen, CrC6alkyl, C3-C8alkoxyalkyl, CrC8hydroxyalkyl, and C7-C12aralkyl and R-, is taken together with Z to form a linkage bond to the polymeric backbone; or Ri and R2 are independently selected from C3-C8alkoxyalkyl, CrC8hydroxyalkyl, and C -C12aralkyl and R is taken together with Z to form a linkage bond to the polymeric backbone; or R-i and R2, when taken together with the nitrogen atom to which they are directly attached in formula (PI), form a ring denoted by formula (ll-Z):
Figure imgf000048_0002
(ll-Z) wherein the ring of formula (ll-Z) 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, d-C3hydroxyalkyl, oxo, C2-C4acyl, C C3alkyl, C2-C4alkylcarboxy, d-C3alkoxy, CrC20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, CrC6alkyl, C2-C4acyl, C2-C hydroxyalkyl and C3-C8alkoxyalkyl; or R and R2, when taken together with the nitrogen atom to which they are directly attached in formulae (PI), (Pl-a) or (Pl-b) 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, wherein the bicyclic ring is substituted with Z; R3 and R4 are independently attached to the cyclohexane ring shown in formulae (PI), (Pl-a) or (Pl-b) at the 3-, 4-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, CrC6alkyl and d-C6alkoxy, and, when both R3 and R4 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; R5, R6 and Rι4 are independently selected from hydrogen, d-C6alkyl, aryl and benzyl, or R6 and Rι4, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-Cι3carbocyclic ring, and ring systems selected from formulae (lll-Z), (IV-Z), (V-Z), (Vl-Z), (Vll-Z) and (VI ll-Z):
Figure imgf000049_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyI,
CrC6thioalkyl, aryl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6alkyl;
Figure imgf000050_0001
(IV-Z) (V-Z) where R10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, C C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C C6alkyl;
Figure imgf000050_0002
(Vl-Z) where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, C C6alkoxy, C2-C7alkoxycarbonyl, C C6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown in formulae (PI), (Pl-a) or (Pl-b) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000050_0003
(Vll-Z) (Vlll-Z) including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; R30 is independently selected from hydrogen; C2-C20alkenyl, C2-C20alkynyl,
CrC20alkyl, aryl, d-C20carboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, d-C20alkylthio, d-C20alkyIsulfonyl or CrC20alkylsulfinyl; each optionally substituted with d-C5alkyl, halogen, d-C5alkoxy or with a phenyl group optionally substituted with halogen, d-C5alkyl or d-C5alkoxy; R27 is independently selected from -CH2- or oxygen; ■^■™ is a valency that is occupied by a residual ROMP active catalyst trace, and n is an integer from 2 to 1 ,000,000. In another embodiment of the invention, the polymer is a compound of the formula (Pll):
Figure imgf000051_0001
wherein: m^ mm is a valency that is occupied by a residual ROMP active catalyst trace; or, ^ m is a valency that is occupied by a capping group, such as CH2 or CR aanRb wherein Ra and Rb are as defined above; and n is an integer from 2 to 1 ,000,000. In another embodiment, the polymer may comprise a compound of the formula (Pill):
Figure imgf000052_0001
wherein: -"■■■ is a valency that is occupied by a residual ROMP active catalyst trace; or, ^"^ is a valency that is occupied by a capping group, such as CH2 or CR aπRb wherein Ra and Rb are as defined above; and n is an integer from 2 to 1 ,000,000. In another embodiment, the polymer is a compound of the formula (PIV):
Figure imgf000052_0002
(PIV) wherein: Prot is a protected alkyl group; ^^^ is a valency that is occupied by a residual ROMP active catalyst trace; or, ■"■■" is a valency that is occupied by a capping group, such as CH2 or CRaRb wherein Ra and Rb are as defined above; and n is an integer from 2 to 1 ,000,000.
P. Administration of the Compounds of the Invention The present invention provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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. The present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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. The present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 0.1mg/mL to 100mg/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. The present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 5mg/mL to 80mg/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. The present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 10mg/mL to 40mg/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. The present invention further provides a composition or medicament that includes one or more polymers of the invention, selected from any of the polymers, or a solvate, pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomeric mixture, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, 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 polymer at a concentration of about 20mg/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. In another embodiment, the present invention provides compositions which include a polymer 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 polymer 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 polymer 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 polymer 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. Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter, simply referred to as a pharmaceutical composition) containing a polymer 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 polymer of the present invention, in association with a pharmaceutically acceptable carrier. 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 polymer in aerosol form may hold a plurality of dosage units. 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 polymers (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. In general, the pharmaceutical composition includes a polymer 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. 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. 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. 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. 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 polymers, 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. 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. A liquid composition intended for either parenteral or oral administration should contain an amount of the inventive polymer such that a suitable dosage will be obtained. Typically, this amount is at least 0.01 % of a polymer 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 polymer. 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 polymer. 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 polymer of from about 0.1 to about 25% w/v (weight per unit volume). 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 polymer is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. 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. The composition in solid or liquid form may include an agent which binds to the polymer 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. 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 polymers 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. 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 polymers of the present invention. The compositions may be prepared by methodology well known in the pharmaceutical art. The polymers 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 polymers 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 polymer for the appropriate mode of employment (e.g., oral or parenteral routes of administration). A composition intended to be administered by injection can be prepared by combining the polymer 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 polymer so as to facilitate dissolution or homogeneous suspension of the polymer in the aqueous delivery system. Surfactants are desirably present in aqueous compositions of the invention because the polymers 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. 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. 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. 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 polymer exhibits opioid activity where such activity may not be desired. The naloxone may antagonize opioid activity of the administered polymer without adverse interference with the antiarrhythmic activity. As another example, a polymer of the invention may be co-administered with epinephrine in order to induce local anesthesia.
E. Utility and Testing of the Polymers of the Invention The present invention provides one or more polymers, or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers 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. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. These polymers 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. 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 ltoι such as Kv4.2 and Kv4.3), and the ultrarapid delayed rectifier current (lKur) such as Kv1.5, Kv1.4 and Kv2.1). The ultrarapid delayed rectifier current (lκur) has also been described as lsus. A second calcium dependent transient outward current (lto2) has also been described. The pathological conditions that may be treated and/or prevented by the present invention may include, but are not limited to, various cardiovascular diseases. 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, ventricular flutter. In one embodiment, the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents. In another embodiment, the present invention provides ion channel modulating compounds that can be used to selectively inhibit cardiac early repolarising currents and cardiac sodium currents under conditions where an "arrhythmogenic substrate" is present in the heart. An "arrhythmogenic substrate" is characterized by a reduction in cardiac action potential duration and/or changes in action potential morphology, premature action potentials, high heart rates and may also include increased variability in the time between action potentials and an increase in cardiac milieu acidity due to ischaemia or inflammation. Changes such as these are observed during conditions of myocardial ischaemia or inflammation and those conditions that precede the onset of arrhythmias such as atrial fibrillation. In 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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. In other embodiments, the cardiac early repolarising currents referred to in the present invention comprise the cardiac transient outward potassium current (l{0) and/or the ultrarapid delayed rectifier current (lKUr)- In other embodiments, the cardiac transient outward potassium current (lt0) and/or the ultrarapid delayed rectifier current (lκur) referred to in the present invention comprise at least one of the Kv4.2, Kv4.3, Kv2.1 , Kv1.4 and Kv1.5 currents. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, or a composition or medicament that includes said polymer or mixture comprising polymers as described above. 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 polymers of the present invention or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, stereoisomeric mixtures, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors or prodrugs thereof, including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; or a composition or medicament that includes said polymer or mixture comprising polymers as described above. As noted above, the present invention provides for utilizing the polymers 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. 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. Accordingly, polymers 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 polymers of the invention are found to have significant activity in modulating various ion channel activity both in vivo and in vitro. In one embodiment, the present invention provides a polymer of the present invention or a composition containing said polymer, 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 polymers, 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. In one embodiment, the invention provides a polymer of the present invention, or composition containing said polymer, 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. In another embodiment, of the present invention, the above-mentioned early repolarising currents comprise the transient outward potassium current (lt0 or cardiac or lA for neuronal) and/or the ultrarapid delayed rectifier current (lKur); and include at least one of the Kv4.2, Kv4.3, Kv2.1, Kvl.3, Kv1.4 and Kv1.5 currents. In another embodiment, the present invention provides a polymer of the present invention, or composition containing said polymer, 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. In yet another embodiment, the present invention provides a polymer of the present invention, or composition containing said polymer, 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. Furthermore, the voltage-activated sodium ion channels comprise the Nav1 , Nav2 or Nav3 series and may be present in cardiac, neuronal, skeletal muscle, central nervous and/or peripheral nervous systems (e.g. hH1 Na). For cardiac sodium channels, in studies on ion channels in isolated human atrial myocytes, polymers of the present invention have been shown to produce frequency-dependent blockade of cardiac sodium channels. In these studies enchanced 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. 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. 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 polymer of the present invention, or a composition containing a polymer of the present invention is administered to a warmblooded animal in need thereof. Some of the diseases and conditions to which the polymers, 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. 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 polymer of the present invention or a pharmaceutical composition containing said polymer. These methods may be used to relieve or forestall the sensation of pain in a warm-blooded animal. 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 polymer of the present invention or a pharmaceutical composition containing said polymer. 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. 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 a polymer 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 polymer under conditions and for a time sufficient to permit modulation of the activity of the channels by the polymer. 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 polymer exhibits opioid activity where such activity may not be desired. The naloxone may antagonize opioid activity of the administered polymer without adverse interference with the antiarrhythmic " activity. As another example, a polymer of the invention may be co-administered with epinephrine in order to induce local anesthesia. In order to assess whether a polymer 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 polymers and compositions. 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 polymer 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 polymer 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 polymer 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. A second test involves administration of a polymer 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. A third test involves exposing isolated rat hearts to increasing concentrations of a polymer. Ventricular pressures, heart rate, conduction velocity and ECG are recorded in the isolated heart in the presence of varying concentrations of the polymer. The test provides evidence for direct toxic effects on the myocardium. Additionally, selectivity, potency and efficacy of action of a polymer can be ascertained under conditions simulating ischemia. Concentrations found to be effective in this test are expected to be efficacious in the electrophysiological studies. A fourth test is estimation of the antiarrhythmic activity of a polymer against the arrhythmias induced by coronary artery occlusion in anaesthetized rats. It is expected that a good antiarrhythmic polymer will have antiarrhythmic activity at doses which have minimal effects on either the ECG, blood pressure or heart rate under normal conditions. All of the foregoing tests may be performed using rat tissue. In order to ensure that a polymer 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 polymer 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 polymer is given as a series of increasing bolus doses. At the same time possible toxic effects of a polymer on the dog's cardiovascular system is assessed. The effects of a polymer 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 polymer reveal the possible presence of sodium and/or potassium channel blockade. The monophasic action potential also reveals whether a polymer widens the action potential, an action expected of a potassium channel blocker. 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 polymer 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 23G needle as applied to the shaved back of a guinea pig (Cavia porcellus) is assessed following subcutaneous administration of sufficient (50 μL, 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 Polymers of the Invention The ion channel modulating compounds used in this 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; and U.S. Published Patent Application No. US2005002693; or may be prepared by methods described herein or by methods known to one skilled in the art. 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. 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., f-butyldimethylsiiyl, f-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include -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. 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. 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. 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. 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: 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 El 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, Wi) with UV detection at 200 nm. A C18 column with 150 x 4.6 mm, 5μ 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 ~100 μg/mL in mobile phase and 20 μL were injected into the HPLC. Purity was expressed in area%. CE analyses were performed using a P/ACE System MDQ (Beckman Coulter, Fullerton, CA,). Uncoated silica capillaries with 60 (50 to detector) cm length and 75 μm 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°C. Samples (~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 x 20 cm, Silica gel 60 F254 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 F254 with Gypsum or aluminum oxide 60P F254 with Gypsum (type E). Preparative HPLC were performed on a Waters Delta Prep 4000 with a cartridge column (porasil, 10 μm, 125 A, 40 mm X 100 mm). GC analyses were performed on a Hewlett Packard HP 6890 equipped with 30 m x 0.25 mm x 0.25 μm capillary column HP-35 (crosslinked 35% PH ME siloxane) and a flame-ionization detector. High-boiling solvents (DMF, DMSO) were Sure/Seal™ from Aldrich, and tetrahydrofuran (THF) and ethylene glycol dimethyl ether (DME) were distilled from sodium-benzophenone ketyl. Organic extracts were dried with Na2SO4 unless otherwise noted. All moisture sensitive reactions were performed in dried glassware under a nitrogen or argon atmosphere. The following general schemes and examples describe methods may be used for preparing polymers as described herein. The reaction steps according to Schemes 1-19 may be used in the preparation of the polymers, or alternate reaction steps may be used. Alternate reaction steps would be readily recognized by one of skill in the art and include the reaction steps described "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", Richard C. Larock, Wiley- VCH: 1999 and in "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure", Jerry March & Michael Smith, John Wiley & Sons Inc: 2001. The polymer or ROMP active catalysts are commercially available or can be prepared by standard known methods as outlined in for example, U.S. Pat. Nos. 5,312,940, 5,342,909, Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 and references cited therein. 7-Oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid may be synthesized by standard methods from the exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride as outlined for example, France M.B, Alty L.T., Earl M.T J. Chem. Ed. 1999, 76, 659. (3,5-Dioxo-10-oxa-4-aza-tricycio[5.2.1.02,6]dec-8-en-4-yl)-acetic acid and derivatives of Λ/-norbornenyl-amino acids and esters may be synthesized by methods outlined for example, Biagini S.C.G, Davies R.G., Gibson V.C., Giles M.R., Marshall E.L, North M., Robson D.A. Chem. Commun. 1999, 235, Biagini S.C.G, Bush S.M., Gibson V.C, Mazzariol L, North M., Teasdale W.G., Williams CM., Zagotto G., Zamuner D. Tetrahedron 1995, 51, 7247, Barrett A.G.M. , Cramp S.M., Roberts R.S., Zecri F.J Org. Lett. 2000, 2, 261, Maynard H.D., Okada S.Y., Grubbs R.H. Macromolecules 2000, 33, 6239 and Arnauld T., Barrett A.G.M., Cramp S.M., Roberts R.S., Zecri F.J. Org. Lett. 2000, 2, 2663. Derivatives of Λ/-norbornenyl-amines may be synthesized by methods outlined for example, Gibson V.C, Marshall E.L., North M., Robson D.A., Williams P.J. Chem. Commun. 1997, 1095. Commercially available norbornene derivatives may be obtained from Sigma- Aldrich and include examples such as but not limited to c/s-5-norbornene-et7θO-2,3- dicarboxylic acid, 5-norbornene-2-carboxylic acid and mono-methylc/s-5-norbomene- et7θO-2,3-dicarboxylate. (3-Hydroxymethyl-7-oxa-bicyclo[2.2.1]hept-5-en-2-yl)-methanol may be synthesized by dehydration followed by reduction of the corresponding 7-oxa- bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (e.g. Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3301). Grubbs catalysts that may be used in ROMP polymerizations below are described in Figure 1 of Barrett A.G.M, Hopkins B.T., Kόbberiing J. Chem. Rev. 2002, 102, 3303, specifically those described in Trnka T.M, Grubbs R.H. Ace. Chem. Res. 2001 , 34, 18 and Schwab P., Grubbs R.H., Ziller J.W. J. Am. Chem. Soc. 1996, 778, 100. Other examples of readily available norbornene derivatives are described in
Figure 2 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3305 and references cited therein. Each reference listed herein and in this section in particular is incorporated herein by reference in its entirety. The variables shown in the figures below, such as R, Z, A and the like have the same meanings as previously stated. In any of the schemes below that list EtOCH=CH2 as a reactant, it is meant that the reactant is an optional reactant, which is a capping group that may cap the polymer with a =CH2 functionality. Other variations, such as the use of other capping reagents that provide other capping groups, such as =CRaRb are evident to those of skill in the art.
SCHEME 1. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXIV) BY CONJUGATION REACTION OF AN AMINOCYCLOHEXYL ETHER (XXXIII) TO REAGENT (XXXII).
Figure imgf000076_0001
R 1 = any suitable functionality capable of conjugation to an aminocyclohexyl ether Prot = protected R group Z" = functional group that gives rise to a linkage group (Z1) upon reaction with (XXXII) EXAMPLE 1 In Scheme 1, a norbornene derivative (1 equiv) (XXXIII) may be dissolved in a suitable solvent and mono-protected with a suitable protecting group (suitable methods are set forth in, for example, Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1991)). The mono-protected linker (1 equiv) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (1 equiv) (XXXIII) in a standard coupling reaction. The resultant mono-linked aminocyclohexyl ether (XXXIV) may be isolated and purified. Similarly, syntheses of monomeric adducts (XXXIV-a) and (XXXIV-b) are shown by illustration but not by way of limitation in Schemes 1a and 1b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXIV). SCHEME 1A. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXIV-A) BY CONJUGATION REACTION OF AN AMINOCYCLOHEXYL ETHER (XXXIII-A) TO REAGENT (XXXII).
Figure imgf000077_0001
(XXXIl) (XXXIV-a) R41 = any suitable functionality capable of conjugation to an aminocyclohexyl ether Prot = protected R group Z" = functional group that gives rise to a linkage group (Z') upon reaction with (XXXII)
SCHEME 1 B. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXIV-B) BY CONJUGATION REACTION OF AN AMINOCYCLOHEXYL ETHER (XXXIII-B) TO REAGENT (XXXII).
Figure imgf000078_0001
(XXXII) (XXXIV-b) R41 = any suitable functionality capable of conjugation to an aminocyclohexyl ether Prot = protected R group Z" = functional group that gives rise to a linkage group (Z') upon reaction with (XXXII)
SCHEME 2. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXVI) BY CONJUGATION REACTION OF AN AMINOCYCLOHEXYL ETHER (XXXIII) TO REAGENT (XXXV).
Figure imgf000078_0002
R41 = any suitable functionality capable of conjugation to an aminocyclohexyl ether Prot = protected R group Z" = functional group that gives rise to a linkage group (Z1) upon reaction with (XXXV) EXAMPLE 2 In a typical reaction, a norbornene derivative (1 equiv) (XXXV) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (1 equiv) (XXXIII) in a standard coupling reaction. The resultant monomer adduct (XXXVI) may be isolated and purified. Similarly, syntheses of monomeric adducts (XXXVI-a) and (XXXVI-b) are shown by illustration but not by way of limitation in Schemes 2a and 2b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXVI). SCHEME 2A. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXVI-A) BY CONJUGATION REACTION OF AN AMINOCYCLOHEXYL ETHER (XXXIII-A) TO REAGENT (XXXV).
Figure imgf000079_0001
R41 = any suitable functionality capable of conjugation to an aminocyclohexyl ether Prot = protected R group Z" = functional group that gives rise to a linkage group (Z') upon reaction with (XXXV)
SCHEME 2B. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXVI-B) BY CONJUGATION REACTION OF AN AMINOCYCLOHEXYL ETHER (XXXIII-B) TO REAGENT (XXXV).
Figure imgf000079_0002
(XXXV) (XXXVI-b) R41 = any suitable functionality capable of conjugation to an aminocyclohexyl ether Prot = protected R group Z" = functional group that gives rise to a linkage group (Z1) upon reaction with (XXXV)
SCHEME 3. SYNTHESIS OF THE MONOMERIC ADDUCT (IXXXX) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII) TO REAGENT (XXXVII).
Figure imgf000080_0001
EXAMPLE 3 In a typical reaction, a norbornene derivative (1 equiv) (XXXVII) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (2 equiv) (XXXIII) in a standard coupling reaction. The resultant monomer adduct (IXXXX) may be isolated and purified. Similarly, syntheses of monomeric adducts (IXXXX-a) and (IXXXX-b) are shown by illustration but not by way of limitation in Schemes 3a and 3b, respectively and are synthesized by methods similar to those described for monomeric adduct (IXXXX).
SCHEME 3A. SYNTHESIS OF THE MONOMERIC ADDUCT (IXXXX-A) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII-A) TO REAGENT (XXXVII).
Figure imgf000081_0001
SCHEME 3B. SYNTHESIS OF THE MONOMERIC ADDUCT (IXXXX-B) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII-B) TO REAGENT (XXXVII).
Figure imgf000081_0002
SCHEME 4. SYNTHESIS OF THE POLYMER PRODUCT (XXXX) BY ROMP OF REAGENT (XXXIV) USING A GRUBBS CATALYST.
Figure imgf000082_0001
EXAMPLE 4 A vial may be charged with the monomer adduct (XXXIV) and a stirbar and degassed. The monomer adduct (XXXIV) may be dissolved in a suitable solvent under a nitrogen atmosphere. Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere. To this may be added the solution of the monomer adduct (XXXIV), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXIV) is polymerized. The resultant polymer product (XXXX) may be washed with a suitable solvent, filtered and isolated. Similarly, syntheses of monomeric adducts (XXXX-a) and (XXXX-b) are shown by illustration but not by way of limitation in Schemes 4a and 4b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXX).
SCHEME 4A. SYNTHESIS OF THE POLYMER PRODUCT (XXXX-A) BY ROMP OF REAGENT (XXXIV-A) USING A GRUBBS CATALYST.
Figure imgf000083_0001
(XXXIV-a)
Figure imgf000083_0002
SCHEME 4B. SYNTHESIS OF THE POLYMER PRODUCT (XXXX-B) BY ROMP OF REAGENT (XXXIV-B) USING A GRUBBS CATALYST.
Figure imgf000083_0003
SCHEME 5. SYNTHESIS OF THE POLYMER PRODUCT (XXXXI) BY ROMP OF REAGENT (XXXVI) USING A GRUBBS CATALYST.
Figure imgf000084_0001
EXAMPLE 5 A vial may be charged with the monomer adduct (XXXVI) and a stirbar and degassed. The monomer adduct (XXXV!) may be dissolved in a suitable solvent under a nitrogen atmosphere. Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere. To this may be added the solution of the monomer adduct (XXXVI), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXVI) is polymerized. The resultant polymer product (XXXXI) may be washed with a suitable solvent, filtered and isolated. Similarly, syntheses of monomeric adducts (XXXXI-a) and (XXXXI-b) are shown by illustration but not by way of limitation in Schemes 5a and 5b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXXI).
SCHEME 5A. SYNTHESIS OF THE POLYMER PRODUCT (XXXXI-A) BY ROMP OF REAGENT (XXXVI-A) USING A GRUBBS CATALYST.
Figure imgf000085_0001
SCHEME 5B. SYNTHESIS OF THE POLYMER PRODUCT (XXXXI-B) BY ROMP OF REAGENT (XXXVI-B) USING A GRUBBS CATALYST.
Figure imgf000085_0002
SCHEME 6. SYNTHESIS OF THE POLYMER PRODUCT (PI) BY ROMP OF REAGENT (IXXXX) USING A GRUBBS CATALYST.
Figure imgf000086_0001
EXAMPLE 6 A vial may be charged with the monomer adduct (IXXXX) and a stirbar and degassed. The monomer adduct (IXXXX) may be dissolved in a suitable solvent under a nitrogen atmosphere. Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere. To this may be added the solution of the monomer adduct (IXXXX), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kόbberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (IXXXX) is polymerized. The resultant polymer product (PI) may be washed with a suitable solvent, filtered and isolated. Similarly, syntheses of monomeric adducts (Pl-a) and (Pl-b) are shown by illustration but not by way of limitation in Schemes 6a and 6b, respectively and are synthesized by methods similar to those described for monomeric adduct (PI). SCHEME 6A. SYNTHESIS OF THE POLYMER PRODUCT (Pl-A) BY ROMP OF REAGENT (IXXXX-A) USING A GRUBBS CATALYST.
Figure imgf000087_0001
SCHEME 6B. SYNTHESIS OF THE POLYMER PRODUCT (Pl-B) BY ROMP OF REAGENT (IXXXX-B) USING A GRUBBS CATALYST.
Figure imgf000087_0002
SCHEME 7. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXXI) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII) TO REAGENT (XXXX).
Figure imgf000088_0001
EXAMPLE 7 In a typical reaction, a norbornene derivative (1 equiv) (XXXX) may be dissolved in a suitable solvent and reacted with an aminocyclohexyl ether compound (1 equiv) (XXXIII) in a standard coupling reaction. The resultant monomer adduct (XXXXI) may be isolated and purified. Similarly, syntheses of monomeric adducts (XXXXI-a) and (XXXXI-b) are shown by illustration but not by way of limitation in Schemes 7a and 7b, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXXI). SCHEME 7A. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXXI-A) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII-A) TO REAGENT (XXXX).
Figure imgf000088_0002
SCHEME 7B. SYNTHESIS OF THE MONOMERIC ADDUCT (XXXXI-B) BY CONJUGATION REACTION OF AMINOCYCLOHEXYL ETHER (XXXIII-B) TO REAGENT (XXXX).
Figure imgf000089_0001
SCHEME 7C. SYNTHESIS OF THE POLYMER PRODUCT (XXXXI I) BY ROMP OF REAGENT (XXXXI) USING A GRUBBS CATALYST.
Figure imgf000089_0002
EXAMPLE 7C A vial may be charged with the monomer adduct (XXXXI) and a stirbar and degassed. The monomer adduct (XXXXI) may be dissolved in a suitable solvent under a nitrogen atmosphere. Grubbs catalyst (1.5 mol %) may be dissolved in a suitable solvent under a nitrogen atmosphere. To this is added the solution of the monomer adduct (XXXXI), a cross-linker (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kόbberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy-ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXXI) may be polymerized. The resultant polymer product (XXXXII) may be washed with a suitable solvent, filtered and isolated. Similarly, syntheses of monomeric adducts (XXXXII-a) and (XXXXII-b) are shown by illustration but not by way of limitation in Schemes 7d and 7e, respectively and are synthesized by methods similar to those described for monomeric adduct (XXXXII).
SCHEME 7D. SYNTHESIS OF THE POLYMER PRODUCT (XXXXI l-A) BY ROMP OF REAGENT (XXXXI-A) USING A GRUBBS CATALYST.
Figure imgf000090_0001
SCHEME 7E. SYNTHESIS OF THE POLYMER PRODUCT (XXXXII-B) BY ROMP OF REAGENT (XXXXI-B) USING A GRUBBS CATALYST.
Figure imgf000090_0002
SCHEME 8. SYNTHESIS OF MONOMER ADDUCT (XXXXIV)
Figure imgf000091_0001
Compound A Prot = protected R group
Figure imgf000091_0003
(XXXXIII)
Figure imgf000091_0002
EXAMPLE 8 Scheme 8 illustrates the synthesis of the monomeric adduct (XXXXIV) using mono-protected 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (XXXXIII) and (1R,2R)-2-[(3/:?)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane Compound A. In a typical reaction, 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (1 equiv) may be dissolved in a suitable solvent (e.g. CH2CI2) and mono-protected with a suitable protecting group (e.g. BnCI, suitable methods are set forth in, for example, Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1991)). Mono-protected 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (1 equiv) (XXXXIII) may be dissolved in a suitable solvent (e.g. CH2CI2) and reacts with (1/-*?,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane (1 equiv) Compound A under standard acylation procedures to generate the ester linkage. The resultant monomer adduct, the mono-ester-linked 7-oxanorbornene (XXXXIV) is isolated and purified.
SCHEME 9. SYNTHESIS OF MONOMER ADDUCT (XXXXVI)
Figure imgf000091_0004
o2H Compound A
(XXXXV)
Figure imgf000091_0005
EXAMPLE 9 Scheme 9 illustrates the synthesis of the monomeric adduct (XXXXVI) using 7- oxa-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (XXXXV) and ^R,2R)-2-[(3R)- hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane Compound A. In a typical reaction, 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1 equiv) (XXXXV) may be dissolved in a suitable solvent (e.g. CH2CI2) and reacts with (\R,2R)-2-[(?>R)- hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane (1 equiv) Compound A under standard acylation procedures to generate the ester linkage. The resultant monomer adduct, the mono-ester-linked 7-oxanorbornene (XXXXVI) may be isolated and purified.
SCHEME 10. SYNTHESIS OF MONOMER ADDUCT (XXXXVI 11)
Figure imgf000092_0001
(XXXXVII)
Figure imgf000092_0002
EXAMPLE 10 Scheme 10 illustrates the synthesis of the monomeric adduct (XXXXVIII) using 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (XXXXVII) and (1R,2R)-2-[(3R)- hydroxypyrrolidinyl]-1 -(3,4-dimethoxyphenethoxy)cyclohexane Compound A. In a typical reaction, 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (1 equiv) (XXXXVII) may be dissolved in a suitable solvent (e.g. CH2CI2) and reacts with (1/:?,2/:?)-2-[(3 ?)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane (2 equiv) Compound A under standard acylation procedures to generate the ester linkages. The resultant monomer adduct, the di-ester-linked 7-oxanorbornene (XXXXVIII) may be isolated and purified.
SCHEME 11. SYNTHESIS OF POLYMER PRODUCT (Pll)
Figure imgf000093_0001
EXAMPLE 11 Scheme 11 illustrates the ring opening metathesis polymerization of -^R,2R)- 2-[(3""?)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane linked via ester linkages to 7-oxa-bicycIo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (XXXXVIII) using Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) to generate the polymer reagent (Pll). A vial may be charged with the monomer adduct (XXXXVIII) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles. The monomer adduct (XXXXVIIII) may be dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere. Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) (1.5 mol %) (A1) may be dissolved in a suitable solvent (e.g. CH2CI2) under a nitrogen atmosphere. To this may be added the solution of the monomer adduct (XXXXVIII), the cross-linker 1,4-bis(exo-norbornenyl-5-yl)benzene (A2) (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy- ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXXVIII) is polymerized. The resultant aminocyclohexyl ether linked polymer (Pll) may be washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated. SCHEME 12. SYNTHESIS OF POLYMER PRODUCT (PIV)
Figure imgf000094_0001
EXAMPLE 12 Scheme 12 illustrates a ring opening metathesis polymerization of mono- protected (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4- dimethoxyphenethoxy)cyclohexane that may be linked via an ester linkage to 7-oxa- bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid using Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) to generate the polymer reagent (PIV). In particular, a vial may be charged with the monomer adduct (XXXXIV) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles. The monomer adduct (XXXXIV) may be dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere. Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) (1.5 mol %) (A1) may be dissolved in a suitable solvent (e.g. CH2CI2) under a nitrogen atmosphere. To this is added the solution of the monomer adduct (XXXXIV), the cross-linker 1 ,4-bis(exo-norbornenyl-5-yl)benzene (A2) (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kόbberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy-ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXXIV) is polymerized. The resultant aminocyclohexyl ether linked polymer (PIV) is washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated. SCHEME 13. SYNTHESIS OF THE MONOMER ADDUCT (XXXXX)
Figure imgf000095_0001
EXAMPLE 13 Scheme 13 illustrates the synthesis of the monomeric adduct (XXXXX) using (3-hydroxymethyl-7-oxa-bicyclo[2.2.1]hept-5-en-2-yl)-methanol and the succinic acid ester of (1f?,2 ?)-2-[(3f?)-hydroxypyrrolidinyl]-1-(3,4- dimethoxyphenethoxy)cyclohexane. (3-Hydroxymethyl-7-oxa-bicyclo[2.2.1]hept-5-en-2-yl)-methanol is dissolved in a suitable solvent (e.g. CH2CI2) and reacts with the succinic acid derivative of (1R,2f?)-2- [(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane (2 equiv) under standard acylation procedures to generate the ester linkage. The resultant monomer adduct (XXXXX) is isolated and purified.
SCHEME 14. SYNTHESIS OF POLYMER PRODUCT (XXXXXI)
Figure imgf000096_0001
(XXXXX) EXAMPLE 14 Scheme 14 illustrates the ring opening metathesis polymerization of the di- succinic ester-(1 -?,2/"?)-2-[(3/**?)-hydroxypyrrolidinyl]-1-(3,4- dimethoxyphenethoxy)cyclohexane that may be linked to (3-hydroxymethyl-7-oxa- bicyclo[2.2.1]hept-5-en-2-yl)-methanol monomeric adduct (XXXXX) to generate the polymer product (XXXXXI) using Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl). A vial is charged with the monomer adduct (XXXXX) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles. The monomer adduct (XXXXX) is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere. Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) (1.5 mol %) (A1 ) is dissolved in a suitable solvent (e.g. CH2CI2) under a nitrogen atmosphere. To this is added the solution of the monomer adduct (XXXXX), the cross-linker 1 ,4-bis(exo- norbornenyl-5-yl)benzene (A2) (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kόbberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy-ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXXX) is polymerized. The resultant aminocyclohexyl ether linked polymer product (XXXXXI) is washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated. SCHEME 15. SYNTHESIS OF MONOMER ADDUCT (XXXXXIII)
Figure imgf000097_0002
(XXXXXII)
Figure imgf000097_0001
EXAMPLE 15 Scheme 15 illustrates the synthesis of the monomeric adduct (XXXXXIII) using mono-protected (3-hydroxymethyl-7-oxa-bicyclo[2.2.1]hept-5-en-2-yl)-methanol (XXXXXII) with the succinic acid ester of (1R,2f?)-2-[(3f?)-hydroxypyrrolidinyl]-1-(3,4- dimethoxyphenethoxy)cydohexane. (3-Hydroxymethyl-7-oxa-bicyclo[2.2.1]hept-5-en-2-yl)-methanol is dissolved in a suitable solvent (e.g. CH2Cl2) and mono-protected with a suitable protecting group (e.g. silyl ether, suitable methods are set forth in, for example, Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1991)). The protected alcohol (XXXXXII) is dissolved in a suitable solvent (e.g. CH2Cl2) and reacts with succinic acid derivative of Compound A (1 equiv) under standard acylation procedures to generate the ester linkages. The resultant monomer adduct (XXXXXIII) is isolated and purified.
SCHEME 16. SYNTHESIS OF POLYMER PRODUCT (XXXXXIV)
Figure imgf000097_0003
(XXXXXIII) (ii) EtOCH=CH2 Prot = protected R group
Figure imgf000097_0004
EXAMPLE 16 Scheme 16 illustrates the ring opening metathesis polymerization of the mono- protected monomeric adduct of the succinic ester of (1r*?-2R)-2-[(3R)- hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane (XXXXXIII) to generate the polymer product (XXXXXIV) using Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl). A vial is charged with the monomer adduct (XXXXXIII) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles. The monomer adduct (XXXXXIII) is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere. Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) (1.5 mol %) (A1) is dissolved in a suitable solvent (e.g. CH2CI2) under a nitrogen atmosphere. To this is added the solution of the monomer adduct (XXXXXIII), the cross-linker 1 ,4-bis(exo- norbornenyl-5-yl)benzene (A2) (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kobberling J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy-ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXXXIII) is polymerized. The resultant aminocyclohexyl ether linked polymer product (XXXXXIV) is washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated.
SCHEME 17. SYNTHESIS OF POLYMER PRODUCT (XXXXXVI)
Figure imgf000098_0001
EXAMPLE 17 Scheme 17 illustrates the ring opening metathesis polymerization of the monomeric adduct (XXXXXV) to generate the polymer product (XXXXXVI) using Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl). A vial is charged with the monomer adduct (XXXXXV) and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles. The monomer adduct (XXXXXV) is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere. Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) (1.5 mol %) (A1) is dissolved in a suitable solvent (e.g. CH2CI2) under a nitrogen atmosphere. To this is added the solution of the monomer adduct (XXXXXV), the cross-linker 1 ,4-bis(exo- norbornenyl-5-yl)benzene (A2) (optionally as required to modify physical properties or to decrease solubility as described in Scheme 1 of Barrett A.G.M, Hopkins B.T., Kόbberiing J. Chem. Rev. 2002, 102, 3303 (20 mol %)) and ethoxy-ethene. The reaction mixture becomes viscous within minutes as the monomer adduct (XXXXXV) is polymerized. The resultant aminocyclohexyl ether linked polymer product (XXXXXVI) is washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated. A vial is charged with the mono-ester-linked 7-oxanorbornene and a stirbar and degassed using an adequate number of freeze-pump-thaw cycles. The mono-ester- linked 7-oxanorbornene is dissolved in a suitable solvent (e.g. toluene) under a nitrogen atmosphere. Grubbs catalyst, CI2(PCy3)2Ru=Ph (Cy=cyclohexyl) (1.5 mol %) is dissolved in a suitable solvent (e.g. CH2CI2) under a nitrogen atmosphere. To this is added the solution of the mono-ester-linked 7-oxanorbornene, the cross-linker 1 ,4- bis(exo-norbornenyl-5-yl)benzene (20 mol %) and ethoxy-ethene. The reaction mixture becomes viscous within minutes as the mono-ester-linked 7-oxanorbornene is polymerized. The resultant aminocyclohexyl ether linked polymer is washed with a suitable solvent (e.g. MeOH, THF or a combination of both), filtered and isolated.
SCHEME 18. SYNTHESIS OF THE SUCCINIC ACID DERIVATIVE OF (1 2R)-2- [(3r?)-HYDROXYPYRROLIDINYL]-1-(3,4- DIMETHOXYPHENETHOXY)CYCLOHEXANE (IXXXXX)
Figure imgf000099_0001
EXAMPLE 18 Scheme 18 illustrates the synthesis of (IXXXXX) using ( R,2R)-2-[(3R)- hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane Compound A and succinic anhydride. (1f?,2R)-2-[(3/:?)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane Compound A is dissolved in a suitable solvent (e.g. pyridine) and reacts with succinic anhydride generating the succinic acid derivative (IXXXXX).
SCHEME 19. SYNTHESIS OF MONOMER ADDUCT (XXXXXV)
Figure imgf000100_0001
EXAMPLE 19 Scheme 19 illustrates the synthesis of the monomeric adduct (XXXXXV) using (3,5-dioxo-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-en-4-yl)-acetic acid and (λR,2R)-2- [(3/*?)-hydroxypyrrolidinyl]-1 -(3,4-dimethoxyphenethoxy)cyclohexane Compound A. (3,5-Dioxo-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-en-4-yl)-acetic acid was dissolved in a suitable solvent (e.g. CH2CI2) and reacts with (" R,2R)-2-[(3R)~ hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane (1 equiv) Compound A under standard acylation procedures to generate the ester linkage. The resultant monomer adduct (XXXXXV) is isolated and purified.
BIOLOGICAL EXAMPLE 1 ASSESSMENT OF ANTIARRHYTHMIC EFFICACY Antiarrhythmic efficacy may be assessed by investigating the effect of a polymer 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 polymer 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). 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. Results of the test polymers may be expressed as values of a given infusion rate in micromol/kg/min. (ED5oAA) 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 polymer(s) is dissolved.
BIOLOGICAL EXAMPLE 2 MEASUREMENT OF CARDIOVASCULAR AND BEHAVIORAL EFFECTS Preparative surgery is performed in Sprague Dawley rats weighing 200-300 gm and anaesthetized with 65mg/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 guage 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. A 15 min observational period is recorded followed by the intravenous infusion regime of the test polymer at an initial dose of 2.0μmol/kg/min (at 1 ml/hr). This rate is doubled every 5 minutes until one of the following effects is observed: a) partial or complete convulsions b) severe arrhythmias c) bradycardia below 120 beats/min d) hypotension below 50mmHg e) the dose exceeds 32 times the initial starting dose (i.e. 64 μmol/kg/min). 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. Estimates of plasma concentrations of the test polymer 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 x g and the plasma decanted. Brain tissue samples are also extracted and kept frozen (-20°C) along with the plasma samples for chemical analysis. Electrocardiograph (ECG) parameters: PR, QRS, QTi (peak of T-wave), QT2 (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 (D25) for all recorded ECG variables is determined. Results of the tests can be expressed as D25 (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) Male Sprague-Dawley rats weighing between 250-350g are used. They are randomly selected from a single group and anesthetized with pentobarbital (65mg/kg, ip.) with additional anesthetic given if necessary. The trachea is cannulated and the rat is artificially ventilated at a stroke volume of 10 mlJkg, 60 strokes/minute. The right external jugular vein and the left carotid artery are cannulated for intravenous injections of polymers and blood pressure (BP) recording, respectively. 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. Two Teflon-coated silver electrodes are inserted through the chest wall using
27G 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 μA) of a square wave stimulus required to capture and pace the heart at a frequency of 7.5 Hz and a pulse width of 0.5msec; 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 x iT and 0.2msec pulse width), MFF is the maximum stimulation frequency (in Hz) at which the heart is unable to follow stimulation (1.5x iT and 0.2msec pulse width); VTt is the minimum pulse current (in μA) to evoke a sustained episode of VT (0.2msec pulse width and 50 Hz) (Howard, P.G. and Walker, M.J.A., Proc. West. Pharmacol. Soc. 33:123-127 (1990)). 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). The initial infusion dose is chosen based on a previous toxicology study of the test polymer in conscious rats. This is an infusion dose that did not produce a 10% change from pre-drug levels in haemodynamic or ECG parameters. 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/h/300g (i.e., O.'5μmol/kg/min). Each infusion dose is doubled (in rate) every 5 minutes. All experiments are terminated at 32 mL/h/300g (i.e., 32 μmol/kg/min). Electrical stimulation protocols are initiated during the last two minutes of each infusion level. Responses to test polymers 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.). D25'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 polymers of the present invention.
* * * * * 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 and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. 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.

Claims

WHAT IS CLAIMED IS 1. A polymer comprising a polymeric backbone and an ion channel modulating compound, wherein the ion channel modulating compound is attached to the polymeric backbone via a direct bond or via a linker moiety.
2. The polymer of claim 1 , wherein the ion channel modulating compound is attached to the polymeric backbone via a linker.
3. The polymer of claim 1 , wherein the ion channel modulating compound is a compound having an aminocyclohexyl ether moiety.
4. The polymer of claim 1 , wherein the polymer further comprises a cross- linker.
5. The polymer of claim 1 , wherein the polymeric backbone is a polymer selected from the group consisting of a homopolymer, a heteropolymer, a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer or any combination of the foregoing.
6. The polymer of claim 1 , wherein at least a portion of the polymeric backbone is produced from a ROMP active monomer.
7. The polymer of claim 6, wherein the ROMP active monomer is a monomer having a cycloolefin moiety.
8. The polymer of claim 7, wherein the ROMP active monomer is selected from the group consisting of substituted or unsubstituted: norbornene, norbornadiene, cyclopentene, dicyclopentadiene, cycloheptene, cyclo-octene, 7-oxanorbornene, 7- oxanorbornadiene and cyclododecane.
9. The polymer of claim 1 , wherein the polymeric backbone is produced by a reaction between a ROMP active monomer and a ROMP active catalyst.
10. The polymer of claim 9, wherein the ROMP active catalyst is a transition metal catalyst.
11. The polymer of claim 1 , wherein the ion channel modulating compound is a compound of the formula (I), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000106_0001
wherein, independently at each occurrence, X is selected from a direct bond, -C(R6,Rι4)-Y- and -C(Ri3)=CH-, with the proviso that when X is a direct bond and A is formula (III), then at least one of R7, R8 and R9 is not hydrogen; Y is selected from a direct bond, O, S and C C alkylene; Rι3 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl; R1 and R2 are independently selected from hydrogen, d-C8alkyl, C3-C8alkoxyalkyl, CrC8hydroxyalkyl, and C7-C12aralkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (I), form a ring denoted by formula (II):
Figure imgf000106_0002
(H) 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, CrC3hydroxyalkyl, oxo, C2-C4acyl, CrC3alkyl, C2-C4alkylcarboxy, d-C3alkoxy, CrC20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, d-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or R-i and R2, 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; R3 and R4 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, d-C6alkyl and CrC6alkoxy, and, when both R3 and R4 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; R5, R6 and R14 are independently selected from hydrogen, d-C6alkyl, aryl and benzyl, or R6 and R1 , when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C 2alkyl, a C3-C13carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):
Figure imgf000107_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, d-Cethioalkyl and N(R15,Rιe) where R15 and Rι6 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6alkyl;
Figure imgf000107_0002
(IV) (V) where Rι0 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C C6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, C C6thioalkyl, and N(Rι5,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl;
Figure imgf000108_0001
(VI) where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, C C6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl, and N(Ri5,Rιe) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 7 when Z is N, and R is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000108_0002
(VII) (VIII) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; wherein the ion channel modulating compound of formula (I) is attached to the polymeric backbone by the substitution of any valency of formula (I) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is in turn bound to the polymeric backbone.
12. The polymer of claim 1 , wherein the ion channel modulating compound is a compound of formula (XXVI), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000109_0001
(XXVI) wherein: Ri and R2 are independently selected from hydrogen, d-C8alkyl, C3- C8alkoxyalkyl, C C8hydroxyalkyl, and C7-C12aralkyl; or are independently selected from C3-C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl; or . R and R2, are taken together with the nitrogen atom to which they are directly attached in formula (XXVI) to form a ring denoted by formula (II):
Figure imgf000109_0002
(II) 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, d- C3hydroxyalkyl, oxo, C2-C4acyl, d-C3alkyl, C2-C4alkylcarboxy, d-C3alkoxy, c C20alkanoyloxy, or may be substituted to form a spiro five- or six membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, CrC6alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3- C8aIkoxyalkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (XXVI), may form a bicyclic ring system selected from 3- azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3- yl and 3-azabicyclo[3.2.0]heptane-3-yl; R2 and R22 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, d- C6thioalkyl and N(R15,Rι6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6alkyl; and — is a bond that provides either an R or an S stereoisomer at the position indicated by the symbol *; wherein the ion channel modulating compound of formula (XXVI) is attached to the polymeric backbone by the substitution of any valency of formula (XXVI) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is in turn bound to the polymeric backbone.
13. The polymer according to claim 1, wherein the ion channel modulating compound is of formula (IX), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000110_0001
wherein, independently at each occurrence, n is selected from 1 , 3 and 4; Q is either O (oxygen) or -O-C(O); X is selected from a direct bond, -C(R6,Rι4)-Y-, and -C(R13)=CH-; Y is selected from a direct bond, O, S, and C C4alkylene; Ri3 is selected from hydrogen, d-Cealkyl, C3-C8cycloalkyl, aryl, and benzyl; R and R2 are independently selected from hydrogen, C C8alkyl, C3-C8alkoxyalkyl, C C8hydroxyalkyl, and C -C12aralkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (IX), form a ring denoted by formula (II):
Figure imgf000111_0001
(II) 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, d-C3hydroxyalkyl, oxo, C2-C4acyl, C C3alkyl, C2-C4alkylcarboxy, CrC3alkoxy, d-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, d-C6alkyl, C2-C4acyl, C2-C hydroxyalkyl and C3-C8alkoxyalkyl; or R- and R2, 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; R3 and R4 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 C6alkyl and d-C6alkoxy, and, when both R3 and R4 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; R5, R6 and R14 are independently selected from hydrogen, CrC6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-d2alkyl, a C3-Cι3carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):
Figure imgf000111_0002
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl and N(R15,R 6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6alkyl;
Figure imgf000112_0001
(IV) (V) where R10 and R are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl;
Figure imgf000112_0002
(VI) where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,Rι6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl; and Z is selected from CH, CH2, 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 R17 when Z is N, and R17 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000112_0003
(VII) (VIII) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; wherein the ion channel modulating compound of formula (IX) is attached to the polymeric backbone by the substitution of any valency of formula (IX) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is in turn bound to the polymeric backbone.
14. The polymer according to claim 1 , wherein the ion channel modulating compound is 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:
Figure imgf000113_0001
wherein, R7, R8 and R9 are independently selected from hydrogen, hydroxy and d-C6alkoxy, as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R7, R8 and R9 cannot all be hydrogen; wherein the ion channel modulating compound of Formula (IA) is attached to the polymeric backbone by the substitution of any valency of Formula (IA) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is bound to the polymeric backbone.
15. The polymer of claim 14, wherein the compound of formula (IA) is attached to the polymeric backbone by the substitution of the hydrogen valency in the r v ' OH moiety with a bond to the polymeric backbone.
16. The polymer of claim 1 , wherein the ion channel modulating compound is Compound A:
Figure imgf000114_0001
or pharmaceutically acceptable salts or solvates thereof; wherein the ion channel modulating compound Compound A is attached to the polymeric backbone by the substitution of any valency of Compound A with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is bound to the polymeric backbone.
17. The polymer of claim 16, wherein the ion channel modulating compound is attached to the polymeric backbone by the substitution of the hydrogen valency in the '"v^ OH moiety with a bond to the polymeric backbone.
18. The polymer of claim 1 , wherein the ion channel modulating compound is attached to the polymeric backbone by a linkage bond selected from the group consisting of an ester, an amide, a carbamate, a urea and a boronate linkage bond.
19. The polymer of claim 4, wherein the cross linker is selected from the group consisting of divinyl benzene, diallyl phthalate, 1 ,4-bis(exo-norbomenyl-5- yl)benzene.
20. The polymer of claim 9, wherein the ROMP active catalyst is a ruthenium based catalyst.
21. The polymer of claim 9, wherein the polymeric backbone comprises a residual ROMP active catalyst trace.
22. The polymer of claim 9, wherein the ROMP active catalyst is of the formula:
Figure imgf000115_0001
wherein: M is Os or Ru; R33 and R34are the same or different and are each independently an anionic ligand; R31 and R32 are the same or different and are each independently a neutral electron donor ligand; and R28 and R29 are each independently hydrogen or a substituent selected from the group consisting of CrC20alkyl, C2-C20alkenyl, C2-C20alkynyl, aryl, CrC20carboxylate, CrC20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, C C20alkylthio, CrC20alkylsulfonyl and CrC20alkylsulfinyl, wherein each of the R28 or R29 substituent groups is optionally substituted with one or more moieties selected from the group consisting of d-C5alkyl, halogen, d-C5alkoxy, and phenyl wherein the phenyl group is optionally substititued with halogen, d-C5alkyl or C C5alkoxy; wherein any two or more R33, R34, R3ι, and R32 catalyst ligands may optionally by taken together to form a chelating multidentate ligand.
23. The polymer of claim 22, wherein R33 and R34 are independently selected from a functional group selected from the group consisting of halogen, hydrogen, CrC20alkyl, aryl, CrC20alkoxide, aryloxide, C2-C20alkoxycarbonyl, arylcarboxylate, CrC20carboxylate, aryl, d-C20alkylsulfonate, C C20alkylthio, CrC20alkylsulfonyl, and CrC20alkylsulfinyl, wherein each functional group is optionally substituted with a halogen, C C5alkyl, C C5alkoxy or phenyl wherein the phenyl group is optionally substituted with a halogen, C C5alkyl, or CrC5alkoxy group.
24. The polymer of claim 23, wherein R33 and R3 are independently selected from the group consisting of CI, CF3CO2, CH3CO2, CFH2CO2, (CH3)3CO, (CF3)2(CH3)CO, (CF3)(CH3)2CO, PhO, MeO, EtO, tosylate, mesylate or trifluoromethanesulfonate.
25. The polymer of claim 24, wherein both R33 and R34 are CI.
26. The polymer of claim 22, wherein R31 and R32 are independently selected from the group consisting a phosphine, sulfonated phosphine, phosphate, phosphinite, phosphonite, arsine, stibine, ether, amine, amide, sulfoxide, carbonyl, nitrosyi, pyridine or thioether.
27. The polymer of claim 26, wherein R31 and R32 are independently selected from the group consisting of PMe3, PCy3, PPh3, P(p-Tol)3, P(o-Tol)3, PMePh2, PPhMe2, P(CF3)3, P(p-FC6H4)3, pyridine, P(p-CF3C6H4)3, (p-F)pyridine, (p-CF3)pyridine, P(C6H4-SO3Na)3 or P(CH2C6H4-SO3Na)3.
28. The polymer of claim 27, wherein both R31 and R32 are PCy3.
29. The polymer of claim 22, wherein both R33 and R34 are CI and both R3ι and R32 are PCy3.
30. The polymer of claim 22, wherein R3ι or R32 is a N-heterocyclic carbene ligand.
31. The polymer of claim 30, wherein the N-heterocyclic carbene ligand is selected from the formulae:
Figure imgf000116_0001
wherein: R35, R36, R37> R38, R39 and R40 are each independently hydrogen or a substituent selected from the group consisting of C C20alkyl, C2-C20alkenyl, C2-C20alkynyl, aryl, d-docarboxylate, CrC20aIkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, CrC20alkylthio, C C20alkylsulfonyl and d-C20alkylsulfinyl, wherein each of the R35, R36, R37, R38, R39 and R40 substituent groups is optionally substituted with one or more moieties selected from the group consisting of C C10alkyl, d-Cι0alkoxy, and aryl, wherein the CrC10alkyl, C Cι0alkoxy, and aryl moieties are optionally substituted with one or more groups selected from a halogen, a d-C5alkyl, C C5alkoxy, and phenyl.
32. The polymer of claim 22, wherein R28 is hydrogen and R29 is phenyl.
33. A polymer comprising an ion channel modulating compound, a residual ROMP active catalyst trace, and a polymeric backbone containing a cycloalkane or heterocycloalkane moiety.
34. The polymer of claim 33, wherein the residual ROMP active catalyst trace is bound to the polymeric backbone as an alkylidene.
35. The polymer of claim 33, wherein the residual ROMP active catalyst trace is derived from a catalyst of the formula:
Figure imgf000117_0001
wherein: M is Os or Ru; R33 and R34 are the same or different and are each independently an anionic ligand; R3ι and R32 are the same or different and are each independently a neutral electron donor ligand; R28 and R29 are each independently hydrogen or a substituent selected from the group consisting of C C20alkyl, C2-C20alkenyl, C2-C20alkynyl, aryl, d-C2ocarboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, C C20alkylthio, CrC20alkylsulfonyl and CrC20alkylsulfinyl, wherein each of the R28 or R29 substituent groups is optionally substituted with one or more moieties selected from the group consisting of Crdalkyl, halogen, d-C5alkoxy, and phenyl wherein the phenyl group is optionally substitituted with halogen, d-C5alkyl or CrC5alkoxy; wherein any two or more R33, R34, R31, and R32 catalyst ligands may optionally be taken together to form a chelating multidentate ligand.
36. The polymer of claim 35, wherein the ion channel modulating compound is a compound having an aminocyclohexyl ether moiety.
37. The polymer of claim 33, wherein the ion channel modulating compound is a compound of the formula (I), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000118_0001
wherein, independently at each occurrence, X is selected from a direct bond, -C(R6,Rι4)-Y- and -C(R13)=CH-, with the proviso that when X is a direct bond and A is formula (III), then at least one of R7, R8 and R9 is not hydrogen; Y is selected from a direct bond, O, S and d-C alkylene; R13 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl; R-i and R2 are independently selected from hydrogen, C C8alkyl, C3-C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl; or R and R2, when taken together with the nitrogen atom to which they are directly attached in formula (I), form a ring denoted by formula (II):
Figure imgf000118_0002
(II) 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, CrC3hydroxyalkyl, oxo, C2-C4acyl, C C3alkyl, C2-C4alkylcarboxy, CrC3alkoxy, CrC20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, d-C6alkyl, C2-C4acyl, C2-C hydroxyalkyl and C3-C8alkoxyalkyl; or RT and R2, 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; R3 and R4 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, d-Cealkyl and d-C6alkoxy, and, when both R3 and R4 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; R5, R6 and R14 are independently selected from hydrogen, d-C6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-C13carbocyclic ring, and ring systems selected from formulae (111), (IV), (V), (VI), (VII) and (VIII):
Figure imgf000119_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C C6alkyl, C C6alkoxy, C2-C7alkoxycarbonyl,
CrCethioalkyl and N(R15,R 6) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and C C6alkyl;
Figure imgf000119_0002
(IV) (V) where Ri0 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C C6alkyl;
Figure imgf000120_0001
(VI) where R 2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, C C6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl, and N(Ri5,R θ) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R 7 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000120_0002
(VII) (VIII) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; and wherein the ion channel modulating compound of Formula (I) is attached to the polymeric backbone by the substitution of any valency of Formula (I) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is in turn bound to the polymeric backbone.
38. The polymer of claim 33, wherein the ion channel modulating compound is of formula (IX), or solvates or pharmaceutically acceptable salts thereof:
Figure imgf000121_0001
wherein, independently at each occurrence, n is selected from 1 , 3 and 4; Q is either O (oxygen) or -O-C(O); X is selected from a direct bond, -C(R6,Rι4)-Y-, and -C(R13)=CH-; Y is selected from a direct bond, O, S, and C C4alkylene; R13 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl, and benzyl; R-i and R2 are independently selected from hydrogen, d-C8alkyl, C3-C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (IX), form a ring denoted by formula (II):
Figure imgf000121_0002
(II) 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, CrC3hydroxyalkyl, oxo, C2-C acyl, d-C3alkyl, C2-C4alkylcarboxy, CrC3alkoxy, CrC20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, CrC8alkyl, C2-C acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or Ri and R2, 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; R3 and R4 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 C6alkyl and CrC6alkoxy, and, when both R3 and R4 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; R5, R6 and R14 are independently selected from hydrogen, CrC6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-C13carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):
Figure imgf000122_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-Cealkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, d-Cethioalkyl and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl and C C6alkyl;
Figure imgf000122_0002
(IV) (V) where R10 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(Rι5,Rι6) where R15 and R 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl;
Figure imgf000123_0001
(VI) where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C C6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,R16) where R15 and R-ie are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl; and Z is selected from CH, CH2, 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 R17 when Z is N, and Rι7 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000123_0002
(VII) (VIII) as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; and wherein the ion channel modulating compound of Formula (IX) is attached to the polymeric backbone by the substitution of any valency of Formula (IX) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is in turn bound to the polymeric backbone.
39. The polymer of claim 33, wherein the ion channel modulating compound is 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:
Figure imgf000124_0001
wherein, R7, R8 and R9 are independently selected from hydrogen, hydroxy and d-C6alkoxy, as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof, with the proviso that R7, R8 and R9 cannot all be hydrogen; and r vr indicates a bond that gives rise to either R or S stereochemistry, and wherein the ion channel modulating compound of Formula (IA) is attached to the polymeric backbone by the substitution of any valency of Formula (IA) with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is bound to the polymeric backbone.
40. The polymer of claim 39, wherein the ion channel modulating compound is attached to the polymeric backbone by the substitution of the hydrogen valency in the " w^ OH moiety with a bond to the polymeric backbone.
41. The polymer of claim 33, wherein the ion channel modulating compound is Compound A:
Figure imgf000124_0002
or pharmaceutically acceptable salts or solvates thereof; wherein the ion channel modulating compound of Compound A is attached to the polymeric backbone by the substitution of any valency of Compound A with a bond to the polymeric backbone, wherein the bond to the polymeric backbone is a direct bond from the ion channel modulating compound to the polymeric backbone or a bond from the ion channel modulating compound to a linkage bond that is bound to the polymeric backbone.
42. The polymer of claim 41 , wherein the ion channel modulating compound is attached to the polymeric backbone by the substitution of the hydrogen valency in the v^ OH moiety with a bond to the polymeric backbone.
43. The polymer of any one of claims 37, 39 and 41 , wherein the ion channel modulating compound is attached to the polymeric backbone by a linkage bond selected from the group consisting of an ester, an amide, a carbamate, a urea and a boronate linkage bond.
44. A polymer comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone comprises a structure of the Formula (PB-1):
Figure imgf000125_0001
wherein: n is an integer from 2 to 1,000,000; R27 is a heteroatom selected from O, N, S, and P, or R27 is CH2; za is an integer from 0 to 10; — indicates a stereochemistry of R or S; w^^m indicates an occupied valency; and ' AΛΓ indicates a bond.
45. The polymer of claim 44, wherein the w ^ bond at positions 1 and 2 are independently bonds to an ion channel modulating compound or to a linker that is in turn bound to an ion channel modulating compound.
46. The polymer of claim 44, wherein za is 0.
47. The polymer of claim 44, wherein R27 is CH2.
48. The polymer of claim 44, wherein R27 is CH2 and za is 0.
49. The polymer of claim 44, wherein R27 is O.
50. The polymer of claim 44, wherein R27 is O and za is 0.
51. A polymer comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone comprises a structure of the Formula (PB-1 a):
Figure imgf000126_0001
Formula (PB-1a) wherein: R27 is a heteroatom selected from O, N, S, and P, or R27 is CH2; — indicates a stereochemistry of R or S; β^lβ indicates an occupied valency; and 'vvrL ' indicates a bond.
52. The polymer of claim 44, wherein one of valencies indicated by the symbol ^"■™ in Formula (PB-1) is occupied by a residual ROMP active catalyst trace or a capping group.
53. The polymer of claim 44, wherein one of the valencies indicated by the symbol i^™β in Formula (PB-1) is occupied by substituents selected from the group consisting of hydrogen; C2-C20alkenyl, C2-C20alkynyl, d-C20alkyl, aryl, d-C20carboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, d-C20alkylthio, d-C20alkylsulfonyl or CrC20alkylsulfinyl; each optionally substituted with d-C5alkyl, halogen, C C5alkoxy or with a phenyl group optionally substituted with halogen, d-C5alkyl or C C5alkoxy.
54. The polymer of claim 44, wherein one of the valencies indicated by the symbol ^™™ in Formula (PB-1) is occupied by substituents selected from the group consisting of hydrogen, methyl and phenyl.
55. A polymer comprising a polymeric backbone and an ion channel modulating compound, wherein the polymeric backbone is derived from monomer units selected from the group consisting of:
Figure imgf000127_0001
(H1) (H2) (H3) wherein: R27 is a heteroatom selected from O, N, S, and P, or R27 is CH2; za is an integer from 0 to 10; — indicates a stereochemistry of R or S; and I is an ion channel modulating compound or a linker that is attached to an ion channel modulating compound.
56. The polymer of claim 55, wherein za is 0.
57. The polymer of claim 55, wherein the monomer units are selected from the group consisting of:
Figure imgf000127_0002
(XXXIV)
Figure imgf000128_0001
(XXXIV-a)
Figure imgf000128_0002
(XXXIV-b)
Figure imgf000128_0003
(XXXVI)
Figure imgf000128_0004
Figure imgf000129_0001
(XXXVI-b)
Figure imgf000129_0002
(IXXXX-a) and
Figure imgf000130_0001
wherein: Prot is a protected alkyl group; X is selected from a direct bond, -C(R6,Rι4)-Y- and -C(Rι3)=CH-; Y is selected from a direct bond, O, S and C C4alkylene; Z is any linkage bond to the polymeric backbone including, but not limited to ester, amide, carbamate, urea and boronate linkages; Rι3 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl; R-i and R2 are independently selected from hydrogen, d-C6alkyl, C3-C8alkoxyalkyl, d-C8hydroxyalkyl, and C7-C12aralkyl and Ri is taken together with Z to form a linkage bond to the polymeric backbone; or Ri and R2 are taken together with the nitrogen atom to which they are directly attached to form a ring denoted by formula (ll-Z):
Figure imgf000130_0002
(ll-Z) wherein the ring of formula (ll-Z) 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, d-C3hydroxyalkyl, oxo, C2-C4acyl, CrC3alkyl, C2-C4alkylcarboxy, C C3alkoxy, d-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, CrC6alkyl, C2-C4acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or Ri and R2 are taken together with the nitrogen atom to which they are directly attached in formulae (XXXIV), (XXXIV-a), (XXXIV-b), (XXXVI), (XXXVI-a), (XXXVI-b), (IXXXX), (IXXXX-a) and (IXXXX-b) to form a bicyclic ring system selected from 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl,
3-azabicyclo[3.1.0]hexan-3-yl and 3-azabicyclo[3.2.0]heptan-3-yl, wherein the bicyclic ring is substituted with Z'; R3 and R are independently attached to the cyclohexane ring shown in formulae (XXXIV), (XXXIV-a), (XXXIV-b), (XXXVI), (XXXVI-a), (XXXVI-b), (IXXXX), (IXXXX-a) and (IXXXX-b) at the 3-, 4-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, d-C6alkyl and CrC6alkoxy, and, when both R3 and R4 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; R5, R6 and Rι4 are independently selected from hydrogen, CrC6alkyl, aryl and benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-C12alkyl, a C3-Cι3carbocyclic ring, and ring systems selected from formulae (lll-Z), (IV-Z), (V-Z), (Vl-Z), (Vll-Z) and (Vlll-Z):
Figure imgf000131_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, CrC6aIkoxy,
C2-C7alkoxycarbonyl, CrCethioalkyl, aryl and N(R15,R16) where Rι5 and R 6 are independently selected from hydrogen, acetyl, methanesulfonyl and d-C6alkyl;
Figure imgf000132_0001
(IV-Z) (V-Z) where Rι0 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyI, C C6thioalkyI, and N(R 5,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C C6alkyl;
Figure imgf000132_0002
(Vl-Z) where R12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, CrC6alkoxy, C2-C7alkoxycarbonyl, CrC6thioalkyl, and N(R15,R16) where R15 and R16 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-C6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and Rι7 is selected from hydrogen, d-C6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000132_0003
(Vll-Z) (VIII-Z) including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; and R27 is independently selected from -CH2- or oxygen.
58. A polymer comprising a compound of the formula (PI), a compound of formula (Pl-a) or a compound of formula (Pl-b):
Figure imgf000133_0001
(Pi);
Figure imgf000133_0002
(Pl-a); or
Figure imgf000134_0001
(Pl-b) wherein: X is selected from a direct bond, -C(R6,Rι4)-Y- and -C(Rι3)=CH-; Y is selected from a direct bond, O, S and CrC alkylene; R13 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl; Ri and R2 are independently selected from C3-C8alkoxyalkyl, d- C8hydroxyalkyl, and C -Cι2aralkyl and R is taken together with Z to form a linkage bond to the polymeric backbone; or Ri and R2 are independently selected from hydrogen, CrC6alkyl, C3-C8alkoxyalkyl, C C8hydroxyalkyl, and C7-d2aralkyI and Ri is taken together with Z to form a linkage bond to the polymeric backbone; or Ri and R2, when taken together with the nitrogen atom to which they are directly attached in formula (PI), form a ring denoted by formula (ll-Z):
Figure imgf000134_0002
(ll-Z) wherein the ring of formula (ll-Z) 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, d-C3hydroxyalkyl, oxo, C2-C4acyl, d-C3alkyl, C2-C4alkylcarboxy, CrC3alkoxy, CrC20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents selected from hydrogen, d-C6alkyl, C2-C acyl, C2-C4hydroxyalkyl and C3-C8alkoxyalkyl; or R-i and R2, when taken together with the nitrogen atom to which they are directly attached in formulae (PI), (Pl-a) or (Pl-b) 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, wherein the bicyclic ring is substituted with Z'; R3 and R4 are independently attached to the cyclohexane ring shown in formulae (PI), (Pl-a) or (Pl-b) at the 3-, 4-, 5- or 6- positions and are independently selected from hydrogen, hydroxy, CrC6alkyl and d-Cealkoxy, and, when both R3 and R are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; R5, Re and R are independently selected from hydrogen, CrC6alkyl, aryl and benzyl, or R6 and R , when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl; A is selected from C5-d2alkyl, a C3-C13carbocyclic ring, and ring systems selected from formulae (lll-Z), (IV-Z), (V-Z), (Vl-Z), (Vll-Z) and (Vlll-Z):
Figure imgf000135_0001
where R7, R8 and R9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, d-C6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, aryl and N(Rι5,R16) where R15 and Rι6 are independently selected from hydrogen, acetyl, methanesulfonyl and C C6alkyl;
Figure imgf000136_0001
(IV-Z) (V-Z) where Rio and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,Rι6) where R15 and Rι6 are independently selected from hydrogen, acetyl, methanesulfonyl, and d-Cealkyl;
Figure imgf000136_0002
(Vl-Z) where Rι2 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, CrC6alkyl, d-C6alkoxy, C2-C7alkoxycarbonyl, CrCethioalkyl, and N(R15,Rι6) where R15 and R e are independently selected from hydrogen, acetyl, methanesulfonyl, and CrC6alkyl; and Z is selected from CH, CH2, O, N and S, where Z may be directly bonded to "X" as shown in formulae (PI), (Pl-a) or (Pl-b) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is selected from hydrogen, CrC6alkyl, C3-C8cycloalkyl, aryl and benzyl;
Figure imgf000136_0003
(Vll-Z) (VI ll-Z) including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof; R30 is independently selected from hydrogen; C2-C20alkenyl, C2-C20alkynyl, CrC20alkyl, aryl, CrC2ucarboxylate, d-C20alkoxy, C2-C20alkenyloxy, C2-C20alkynyloxy, aryloxy, C2-C20alkoxycarbonyl, CrC20alkylthio, CrC20alkylsulfonyl or CrC20alkylsulfinyl; each optionally substituted with d-C5alkyl, halogen, C C5alkoxy or with a phenyl group optionally substituted with halogen, CrC5alkyl or d-C5alkoxy; R27 is independently selected from -CH2- or oxygen; ^^™ is a valency that is occupied by a residual ROMP active catalyst trace, and n is an integer from 2 to 1 ,000,000.
59. The polymer of claim 58, wherein the polymer is selected from a polymer of the formula (Pll), a polymer of formula (Pill) and a polymer of formula (PIV):
Figure imgf000137_0001
Figure imgf000138_0001
(PIV) wherein: is a valency that is occupied by a residual ROMP active catalyst trace; or, m ~m is a valency that is occupied by a capping group, such as CH2 or CRaRb wherein Ra and Rb are as defined above; and n is an integer from 2 to 1 ,000,000.
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