Title of Invention	BENZOYL BENZOFURANE DERIVATIVES FOR TREATMENT OF CARDIAC ARRHYTHMIA
Abstract	The subject invention pertains to novel compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias. The subject invention further concerns a method of making the novel compounds. The novel compounds are rapidly metabolized analogs of amiodarone, having the distinct and advantageous characteristic of being metabolized to a less lipophilic compound. The new compounds can have particular utility for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure (CHF). The product can also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways.

Title of Invention

BENZOYL BENZOFURANE DERIVATIVES FOR TREATMENT OF CARDIAC ARRHYTHMIA

Abstract

The subject invention pertains to novel compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias. The subject invention further concerns a method of making the novel compounds. The novel compounds are rapidly metabolized analogs of amiodarone, having the distinct and advantageous characteristic of being metabolized to a less lipophilic compound. The new compounds can have particular utility for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure (CHF). The product can also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways.

Full Text	PESCMPTJQN NOVEL COMPOT JNDS FOR TREATMENT OF C^^RDIAC A3^T?HYTHMIA. SV>JTHRSIS. AND METHODS OF USE Cross-Reference to Rftlated Applications This application is a contmuation-in-pait of co«pendiBg application Serial No. 09/211,246, filed December 14, 1998; which is a ciivisdon of application Serial No. 08/465,602, filed June 6,1995» now U.S. Patent No. 5,849,788; which is a division of application Serial No. OS/260,869, filed June 16,1994, IK>W U.S. Patent No, 5,440,054; which is a continuation-in-part of application Serial No. 08/078,371., filed June 16,1993, now U.S. Patent No. 5,364,880. Background of the Invention Congestive heart failure (CHF) is a disease aiifecting approximately 2% of the population of the United States (Sanii, M.H. [1991] 1 Clin, Pharmacol 31:1081). Despite advances in the diagnosis and treatment of CHF, tlae prognosis remains poor with a 5-yesar mortality rate higher tiian 50% fi^m the time of diagnosis (McFate Smith, W. [1985] Am. J. Cardiol 55:3A; McKee, P.A., W-P. Castelli, P.M, McNamara, W,B. Kannel [1971] K Engl 1 Med, 285:1441). In patients willi CHF, the rate of survival is lowest in those patients wifh severe depression of left ventricular function and patients who have fi-equent ventricular arrhythmias. Patients with ventricular arrhythmias and ischemic cardiomyopatiiy have an increased risk of sudden death. The presence of ventr].cular tachycardia in patients with severe CHF resiilts in a three-fold increase in sudden death compared to those without tachycardia C-Bigger, J.T., Jr. [1987] Circulation 75(supplIV):28). Because of the high prevalence of suddsn unexpected death in patients with (^HF, there has been a growing interest in the prognostic significance of arrhythmias in these patients. Several compounds have been used in the management of cardiac anrhythniias in patients with congestive heart failure. Unfortunately, antiarrhyttunic dmg therapy has been disappointing. The efficacy of antiarrhythmic cbiigs markedly decreases as left ventricular function declioies, such that only a small fraction of patients with CHF are responsive to autiairhythxnic therapy. No antiarrhythmic drug has prevrated sudden death in patients with CHF. There is even a question of increased mortality associated with certain antiarrhythmic drugs (the CAST investigators [1989] N, Engl 1 Med, 321:406). Scientists define tachycardia and ventricular fibrillation as being of multiple nature. It now seems clear, and is accepted in the art> that re-entry is the underlying mechanism to mt:>st sustained arrhythmias. Prolonging ventricular repolarization as a means of preventing ventricular arrhythmias has consequently received renewed attention. This pointis to Class-m agents as drugs of choice in the treatment of arrhythmias. A Class-IE agentj as referred to herein, is an agent which is classified as such in the Vaughan-Williams classification of antiarrhythmic drugs. A Class-HI agent exerts its primary antiatihythmic activity by prolonging cardiac action potential dxiration (APD), and thereby the effective refractory period (ERP), with no e:Sect on conduction. These • electrophysiological changes, which are brou^t about by blockade of cardiac potassium chamiels, are well known in the art. Because the blockade of cardiac potassium channels is not associated with depression of the contractile function of the heart, Class-HI agents are pjirticularly attractive for use in patients with CHE'. Unfortunately, the existing Class-Hi agaits are limited in their utihty by additional phaima^:ological activities, lack of good oral bioavailability^ or a poor toxicity profile. The only two Class DI agents currently marketed are bretylium (i.v. only) and amiodarone (i.v. and p.o.). Amiodarone is an antiarrhythmic agent having vasodilator properties that may beneiit patients with severe heart failure. Amiodarone has been shown to improve survival of post-myocardial infarction patients with asymptomatic high-grade ventricular arrhyifamias, and it proved efficacious in patients resistant to other antianhythmic drugs without impairing left ventricular fimction. Cardioprotective agents and methods which employ amiodarone in synergistic combination with vasodilators and beta blockers have been described for use in patients with coronary iiisufaciency (U.S- Patent No. 5,175,187). Amiodarone has also been described for reducing arrhythmias associated with CHF as used in combination with antihypertensive agents, e.g., (S)-l-[6-ataino-2- [[hydroxy(4-pbenylbutyl)phosplimyl3oxyl]-L-proline (U.S. Patent No. 4,962,095) and zofenopril (U.S. Patent No. 4,931,464). However, amlodarone is a difficult drug to managie because of its numerous side effects, some of wMch are serious. The most serious long-term toxicity of amxodarone derives from its kinetics of distribanoD and elimination. It is absorbed slowly, ^ith a lew bioavailability and relatively long hiilf-Iife. These characteristics have clinically importioit consequences, including the necessity of giving loading doses, a delay in the achievemejit of full antiarrhythmic effects, and a protracted period of elimination of the drug aftesr its administration has been discontinued. Amiodarone also can interact negatively with numerous drugs including aprindiae, digoxin, flecainide, pbenytoin, procainamide, quinidine, and warfarin. It also has pharmacodynamic interactions with catecholamines, diltiazem, propranolol, and quinidine, resulting in alpha- and beta-antagonism, sinus arrest and hypotension, bradycardia and sinus £iirest> and torsades de pointes and ventricular tachycardias, respectively. There is also e>ddence that amiodarone depresses vitamin K-dependent clotting factorSj thereby enhant:ing the anticoagulant effect of warfarin. Numerous adverse effects limit the clinical applicability of amiodarone. Important side eifects can occur including corneal microdeposits, hy{)erthyroidism, hypothyroidism, hepatic dysfunction, puhnonary alveolitis, photosensitivity, dermatitis, bluish discoloration, and peripheral neuropathy. There is no Class-m agent presently marketed that can be used safely in patients with CHF. The cardiovascular dmg market is the largest in any field of drug research, and a an effective and safe Ciass-HI antiarrhythmic agent useful in patients with CHF is expected to be of substantial benefit. Therefore, a drug which could successfully improve the prognosis of CHF patients, but vdth a safety profile much improved over that of amiodarone, would be extremely usefiil and desired. Brief SuTTimarv of the Invention The subject invention pertains to novel compounds, and compositions comprising the compounds, for the trcatnaent of cardiac arrhythmias. The subject invention further concerns a method of making the novel compounds. The novel compounds are rapidly metabolized analogs of amiodarone> having the distinct and advantageous characteristic of bexQg metabolized to a less Upophihc compound. This results in an improved safety profile. The new compounds can have particular utility for treating life-threatening ventrisular tachyarrhythmias, especially in patients with c^ongestive heart failure (CHF). The product can also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation imd re-entrant tachyarrhythmias invohang accessory patliways. More specifically, the novel compounds have ihe particular advantage of reducing the numerous side effects observed with the drugs currently available for treatment of these cardiac arrhythmias. For example, the compound of choice cuirently used for • treating cardiac arrhythmias is amiodarone, which has side effects that can be serious. Also disclosed are novel synthesis procedures for the production of the novel compounds. One of the novel syntliesis procedures essentially involves acylation of salicylaldehyde followed by cyclization and chain elongation reactions to form methyl-2-b^izcfiiraneacetate. This compound is reacted with p-anisoylchloride involving a Friedel-Craftsi type reaction which can use SnCl4 as a catalyst. Tlie compound resulting from the Friedtil-Crafts reaction is then converted from the acetate to its carboxylic acid form. The methc«ybenzoyl moiety of the compound is also convert An alternative s>'nthesis procedure, which also uses salicylaldehyde as a starting compound^ involves a cyclization step to form 2-acetylben2ofuran. This compound is then conv«5rted to its thiomorpholide derivative, which can be further converted to 2- benzoiurane acetic acid, which is also formed in the other described synthesis procedure^ The synthesis procedures are identical after formation of 2-benzofurane acetic acid. The subject invention thus involves the innovative development of a Class-Hi antianhythrnic agent having significantly lower toxicity than any currently available compc'imd useful in patients with congestive heart failure (CHF). Brief P?scriptio\|} ofthe Pr^wjngs Figures lA and IB show the step-wise reaction scheme which results in the synthesis of the novel compound, methyl 2-[3-(3,5-diiodo-4-diethylaminoethoxybenz,oyl)benzofurane]acctate and its hydrochloride salt form. Figure 2 shows an alternative synthetic scheme, "vvhere 2-benzofurane acetic acid, compciund 7, can be made fay synthesizing 2-acetylbenzofuran M from salicylaldehyde, follo^^'ed by a chain elongation procedure known as the Willgerodt-Kindler reaction in order to make the thiomorpholide derivative 14 which is then hydrolyzed to compound 7. Figures 3A-3D show the time coxuse of ttie electrophysiological effects of equini.oiar concentrations of compound A and amiodarone in spontaneously beating guinea pig hearts. Figure 3 A is the change in atrial nite versus time plots for equin^olar concejitrations of amiodarone (v) and compound A («)»versus a control (o). Figure 3B is the change in atrioventricular (AY) interval plots for eqtiimolar concentrations of amiodarone (v) and compound A (♦), versus a control (o). Figure 3C is the change in QRS interval (intraventricular conduction time) plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o). Figure 3D is the change in QT interval (repolarization time) plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o). Figures 4A-4D show the time course of the electrophysiological effects of equimolar concentrations of compound A and amiodarone in atrially-paced guinea pig hearts. Figure 4A is the change in S-H interval (atrioventricular nodal conduction time) plots for equimolar concentrations of amiodarone (#) iand compound A (v), versus a control (o). Figure 4B is the change in HV interval (His-Purkinje conduction time) plots for eqiiimolar concentrations of amiodarone (•) and compound A (v), versus a control (o). Figure 4C is tiie change in QRS interval (intraventricular conduction time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (c). Figure 4D is the change in QT interval (repolarij^ation time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (o). Figure 5 shows time course of the electrophysiological effects of amiodarons (5 p.M) m atrially-paced guinea pig hearts. Detailed Disclosure of the Invention The subject invention concerns novel compounds which can produce the desired pharmacological properties of amiodarone but, unlike luniodarone, are susceptibk to biotransformation by plasma and tissue esterases to give a carboxylic acid metabolite. Carboxylic acids can forai water-soluble salts at physiological pH, and therefore can undergo renal ehmination. As a consequence, the novel compounds, cxemphfied herein by compound A, can have shorter elimination half-Ufs, Accordingly, long-term toxicity symptoms (pulmonary fibrosis, corneal microdeposits, t?tc.) decrease. One novel compound of the subject invention, when Zi and Z2 are iodine in Formula I, has the chemical name methyl 2"[3-(3,5-diiodc>-4-diethylaminoethoxyben2oyl)benzofurane] acetate. Compounds of the invention have the cherrical structure; wiierein Zj and Zj maybe the same, or different^ md are a halogen selected firom the group consisting of iodine, fluorine, bromine, and cWorine and X is 0, S, or NH; m has a value from 0-10; R=H, OH^NHj, SH» halide, allcyl, 0-alkyl, acyl, (3-acyl, axyl, 0-aiyl, substituted amine, or substituted thiol; Y - OR,, wherein Rj is a ^straight or branched chain alkyi or heterci alkyl having 1 to 8 carbon atoms, a substituted or unsubstitated axyl or heteroaryl, wherein R>, and R3 are independently selected firom H. alkyl or heteroalkyl of 1 to 6 carbon atoms; or m has a value from 0-10; R„ Rj, and/or Rj may also be a moiety selected from the group consisting of C^2o ^^^> Cfl^Q heteroaHcyU C2.20 aUcenyl, aryl, C,.2o alkyl-aryl, C;j^o alkenyl-aryl, hetei'oaryl, C^,2Q allcyl-heteroaryl, C2.20 alkenyl-beteroarjd, cycloalkyl heterocycloalkyl, Ci,2o alkyl-heteroycIoaDcyl, and Cj^jo alkyl-cycloalkji, my of which may be, optionally, substituted with a moiety selected from the group consisting of C^_6 alkyl, halogen, CN, NOj^ or S02^, or wherein N is part of a cyclic or heterocyclic group, pref 5raitially, but not limited to, morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, azijidine, thiazolidine, thiazoline, tbiadiazoiidine, or tbiadiazoline. The value for n may be from 1 to 19. R2 and R^ may be the same or different. In one embodiment, when Ri is a straight, or branched-chain alkyl or heteroalkyl, it contains at least 9 carbon atoms (n-9). In another embodiment, when R2 and R3 are alkyl or heteroalkyl moieties, they each contain at huast 7 carbon atoms (n=7). In another embodiment, m may have a value from 0 to 10. In a preferred embodiment, m is 4- In another preferred embodiment, m is 3. In a more preferred embodiment, m is 2. In an even more preferred embodiment, m is 0. In the most preferred embodiment, m is 1. In another embodiment, the" structure includes an iodinated benzene ring moiety. It would be understood by an ordinarily skilled artisan that oilier halides, including fiuoriae, bromine, or chlorine, can be substituted for lie iodine substituents. Thus, these other halogenated compounds axe contemplated to be included as part of the invention. In cms embodiment, when Zj and 2^ are the same, both Zj and Zj may not be iodine. Because n can be from 1 to 19^ the term "C„.jo alkyl" refers to straight or branched chain alkyl moiety having from one to twenty carbon atom^., including for example, methyl, ethyl, propyl, isopropyl, butyl, lert-butyl, pentyl, hexyl and the like. In onu embodiment, n is at least one, in an altemati\^e embodiment, n is at least 2. The term 'C2.2o alkenyl" refers to a straight or branched chain alkyl moiety "U^vK^^ 4->.«^ 4-« ^-•.■r^^-a-i-. AiK-tl^A-M /ff/H-t-Mn fsinA 1t n-i r'l v^ iV + ^a-^P^ fSVJ-LJA VVVU LW bVVWAXfcjr VM-bWWk t4tVt-f4-t-4'iJ hMA«i 4-ftM T «.A^ n^t, «V>.«H-'V -^^^.V k^wovwaw w-r •«■- would include for example, vinyl, l-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc. The terai "cycloalfcyl" refers to a saturated alicyclic moiety having from three to six csrbon atoms and which is optionally ben^ofiased at any available position. This temi includes for example cyclopropyl, cyclobutyl, cyclop entyl, cyclohexyl, indanyl and tctralydronaphthyl. The tenn "heterocycloalkyl" refers to a saturated lieterocycUc moiety having from three to six atoms. One or more of these atoms maybe heteroatoms selected from N, 0, S and oxidized versions thereof, and which is optionaJly benzofused at any available positi.on. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl and tetrabydroquinolinyl. The temi "cycloalkenyl" refers to an ahcyclic moiety having from three to six carbc»n atoms and having at least one double bond. This term includes, for example-, cyclopentenyl and cyclohexenyl. The tenn "heterocycloalkenyl" refers to an alicyclic moiety having &om three to sbc atoms. One, or more, of these atoms may be heteroatoms selected from H O, S and oxidized versions thereof, and having in addition one double bond. This terai includes, for exanrple, dihydropyranyl The tenii "aryl" refers to an aromatic carbocyclic radical having a single ring or two condensed rings. This tenn includes, for example phenyl or naphthyl. The tenn "heteroaryl" refi^ to aromatic ring systesms of five to ten atoms of which at leiist one atom is selected from 0, N and S, and includes^ for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The temi "cycloimidyl" refers to a saturated ring of five to ten atoms containing the atom sequence -C(=0)NC(=0)-, The ring may ho optionally benzofused at any available position. Examples include succinimidoyl, phthalimidoyl and hydantoinyl, The term '^benzofiised" refers to the addition of a brazene ring sharing a common bond with the defined ring system. The temi "optionally substituted" means optionally substimted with one or more of thi5 groups specified, at any available position or positions. The temi "halogen" means fluorine, chlorine, bromine or iodine. The novel compounds can also be provided in their salt form. Thus, the invention includes pharaiaceutically acceptable salts, for example acid addition salts derived fiom inorg;amc or organic acids^ such as hydrohlorides, hydrabromides, p-toluenesulfonates, phosphates, sulfates, perchlorates, acetates, trifluoroi acetates, proprionates, citrates^ malC'Uates, succinates, lactates, oxalates, tartrates, and benzoates. Salts may also be deri\'ed from bases (organic and inorganic), such as alkali metal salts (e.g., magnesium or calcium salts), or organic amine salts, such as morphtoHne, piperidine, dimethylamine, or dietfcylamine salts. In addition, the ring structure moieties of the novel compounds can be dkdvatized by methods and procedures well known by those of ordinary skill in tl:ie art. For example, it would be well known that various R-groups can be attached to the six-membered ring of the benzofijran moiety of the subject cx)mpound, wherein the R groups can :include H, OH, NH^, SH, halides, alkyl, O-aHc/l, a^cyl, 0-acyl, aryl, 0-aiyl groups, substituted amines, and substituted thiols. In a preferred embodiment, R is H and X is 0. The subject invention encompasses the novel compound A and compositions comprising these compounds. The successful appHcation of the new compounds to the treatment of CHF is evidenced by the evaluation of the liiermodynamic properties of the compound, e.g., measuring its partition coefficient between water and octanol, evaluation of its kinetics of eliminatioii by measuring its stability in buffer and in human plasina» and evaIi:ation of its electrophysiological properties in guinea pig heart preparations. See Examples hereinbelow. More specificaUy, the novel corapounds can be used for treating life-tiareatening ventricular tachyairhythmias, especially in patients with congestive heart failu3'e. This prodxxct can provide effective management of not only ventricular tach>arrhythniias and less severe ventricular arrhythmias, but also atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways. A composition comprising a novel compound having a rapid elimination rate can offer many advantages over the cunently available antiarrhythmic agents such as aim'odarone. These advantages include: (i) a shorter onset of action, (ii) decreased and more manageable long-term toxicity, and (ill) lower potential for drug int^-actions. In addition, the novel compounds can be included in a composition comprising a second active ingredient The second active ingredient can be useful for concurrent or syneigistic treatment of arrhythmia or for the treatment of an unrelated condition which can be present with or resuU from arrhythmia or CIEF. The subject compounds have thermodynamic properties similar to those of amiodaronCj as suggested by log P measurements, but provide the advantageous property of being rapidly metabolized in plasma to a water-soluble metabolite. More specifically, the subject compounds are Class-IU agents with electronic^ steric, and thennodynamic proptsrties comparable to those of amiodarone, but with an enzymatically labile ester group advantageously binlt into the structure such that the dmg can be readily hydrolyzed in plasma to a polar, water-soluble metabolite. TMs ^vater-soluble metabolite can be eliminated by the kidneys. This is a definite advantage over axniodarone, which is metabolized primarily in the liver. Under such conditions, the elimination of the novel compound A is increased and results in a more rapid dissociation of the dmg fi-om phosjphoUpid-binding sites. The accumulation of the compoundj which is dependent on the sveady-state tissue concentration of the drug, and theiefore on the dose, then becomes easily reversible. It follows that, upon discontinuation of a drug comprising one of the novel compoiinds, clearance from the body is more rapid. This increased elimination makes antiarrhythmic therapy using the subject compounds or compositions compnsmg the subject compounds easi«' to manage. Furtbermore, ttie compounds of the invention may be administered in conjunction with other compounds, or compositions thereof. These compounds, and compositions thereof, may include additional compounds known to be useful for the treatment of cardiac arrhythmias^ cardioprotective agents, antibiotics, antiviral agents, or thrombolytic agents (e,g-, streptokinase, tissue plasminogen activator, or recombinant tissue plasioinogen activator). The compounds and compositions of the invention can have particular usefiilness for treating life-threatening venlxiciJar tachyarrhythmias, especially in patients with congestive heart failure (CHF). Post-mj^ocardial infarction patients can also benefit from the administration of the subject compounds and compositions; thus, methods of treating post-myocardial infarction patients lire also provided by the subject invejition. An "individual" includes animals and huraans in need of treatement for anythmias. In a preferred embodiment, the individual is a human. Cardioprotective agents include vasodilators and beta blockers described for use in patients with coronary insufficiericy (such as those of U.S. Patent No. S^nSjlS? or othe-rs known to the skilled artisan). Other cardioprotective agents include known anti-hypertmsive agents, e^g., (S)-l-[6-atnino-2-[[bydroxy(4-pbenylbutyl)phosphinyl}oxyl]-L-proline (ILS. Patent No. 4,962,095) and zofenopiil (US, Patent No. 4,931,464), Additional cardioprotective agents include, but are not limited to, aspirin^ heparin, warfarin, digitalis, digitoxin, nitroglycerin, isosorbide dinitrate, hydralazine, nitmprusside, captopril, enalapril, and lisinopril The compounds and compositions also provide effective management for ventricular axrhythmias and supraventricular arrhythmias, uicluding atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways. Compounds and compositions of tlie invention are also useful for the treatment of ventricular and supra-ventricular arrbythnnas, including atrial fibrillation and fiuttei; paroxysmal supraventricular tachycardia, ventricular premature beats (VPB). sustained and non-sustained ventricular tachycardia (VT), and ventricular fibrillation (VF), OtisLcr non-limiting examples of the arrhythmias which tnay be treated by the compounds of the instant invention include: naiTow QRS tachycardia (atrial, intra- /para-^ A-V node, or accessory patfaway),ventricular tachycjirdia, and veatricular arrhythmias in cardiomyopathy. Following are examples which ilhistrate procedures, including the best mode, for practicing the invention. These examples should not be construed as lirmting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted. Example 1 - Svntfae&is of the Novel Compound The novel compounds can be synthesized according to the scheme set ou: in Figures lA and IB. Below, the steps of the procedure, as shown in Figures lA-lB, are described in detail. The primary compounds involved, in the synthesis step are numbersd corresponding to the numbers provided in Figures 1A and IB. Methyl o-fornivlphenoxvacetate: 2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erleimieyer flask with powdsred potassium carbonate (569 g), dimethylfonnamide (1,000 ml), and methyl chioroacetate (478 g) and mechanically stirred at 65 ^'C for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25 "^C. Tlie mixture was poured into cold water (0 ""C) while stirring vigorously. An oil separated that suddenly solidified. Stining was continued for 30 minutes and the solid isolated by filtratioa The product was washed with water (2 x 1,000 ml) and pressed dry. The product can also be dried iii vacuo at 25 ""C. A small sample (approx. 2 g) was purified by iiistillation. The boiling range of the pure product is 124-12S 'C at 2 mm Hg and has a melung temperature range of about 50.2'50.6^C. Methyl 2-benzofiiranecarboxylate; 3, The crude product 2 was placed into a 5-liter 3-necked round-bottomed flask equipped with a mechanical stirrer and a water trap. Toluene (1,900 ml) was added and the solution heated at reflux temperature (111 °C) until all water had been removed. Diazabicyclounde-V-ene (T)BU) (65 g) was then added and the mixture was stirred at 111 °C, without the water trap, until the starting material was no longer present, i.e., was not detectable by TLC monitoring. Most of the solvent (90%) was then distilled off. The residue was cooled to 25 ""C, and ethyl acetate (1,000 ml) was added. The mixtxire was transferred to a separator funnel and the organic Solution washed with2NHQ (2x l.OOOnil), then with water (1,000 ml). Diying was done over magnesium sulfate. The crude product (326.56 g) was a dark oil and was "used directly in the next step. A small sanaple was purified for the purpose of structure elucidation: the crude material (2 g) was dissolved in ethyl ether and washed with 1N KOH. Drying was done over magnesium sulfete, the material was filtered, and the solvent evaporated. The oily residue was crystallized from isopropanoU The melting range is 53,8-54"^C. 2-Hydroxvmethylfa^"zofi^^^" ^- The crude product 3 (324 g) was dissolved in anhydrous ethyl ether. The solution was kept under inert atmosphere (nitrogen or argon) and cooled to O^C in an ice bath, AIM solution of lith:ium alnminum hydride in ether (620 ml) was added dropv^e, while stiningi, over a period of 1 hour. The solution was then washed with 2 N HCl (4 x 1,000 ml), with 2 N KOH (2 x 500 ml), and with water (1,000 ml). The material was dried over magnesium sulfate, filtered, and the solvent evapc»rated. The crude product was distilled in vacuo, yielding approximately 155.36 g (1.05 mol). The boiling point is ll6'C at 1.5 mm Hg. 2-Ch)oromethvlbenzofiiran: 5. Compourid 4 (155.25 g) was dissolved in anhydrous ethyl ether (250 ml) containing dimethylformiamide (1 ml). The reaction flask was :?Iaced into an ice bath, and when the solution temperature was between CC and 4'C, thionyl chloride (124.3 g, 76.2 ml) was added diopwise, while stirring, over the pericd of 1 hour. The mixture was then stirred for anotb;er hour, washed with water (250 ml), 3% sodium bicarbonate solution (250 ml), and v;^ith water again {250 ml). The material was dried over magnesium sulfate, filtered, and the solvent evaporated. The product was distilled in vacuo, and the yield was approximately 117 g. The boiling point is about 78 °C at 1.5 mmHg. 2->CvanDmelhvIben2:ofuran: 6. Compound 5 (117 g) was added dropwise to a stining suspension of sodium cyanide (37.64 g) iu dimethyl sulfoxide (100 ml). The reac:tor was placed Scom time to time into an ice bath in order to keep the reaction temperature between20'Cand45'C. Addition lasted 60 minutes. The reaction mixture was stirred for another 16 hours, then poured into methylene chloride (500 ml), washed with water (500 ml, then 2 x 250 ml), and evaporated to dryness. A small sample was purified on a silica gel colimm, eluting with dichloromethane/hexanes (50:50 v/v). 2-Benzofiiraneacetic ^cid: 7. The crude cyanQmethylben2X)fi2raii, compound 6, was stirred for 6 hours in boiling water (1,000 ml) coutaming sodium hydroxide (SO g), cooled to 25 °C, then washed with methylene chloride (250 ml, then 2 x 100 ml). The pH was trought to 2.0 with 6 N HCl. The precipitate was extracted with methylene chloride (200 ml, tiien 100 ml, then 50 ml), dried over magnesium sulfate and the solvent evaporated. The yield was approximately 72 g. Methvl 5'benzQfiiran.eacetate: S. Compound 7 (72 g) was dissolved in methanol (200 ml) and the solution saturated with dry HCl Tlie solution was refluxed for 2 hours and tie solvent evaporated The residue was dissolved in methylaie chloride (200 ml) and the solution washed with 5% sodium bicarbonate, and then with water (100 ml). The residue was dried over magnesium sulfate and the solveit was evaporated. The product was distilled in vacuo. The yield was approximately 67.3 g. Methvl 2-f3-amsovIbenzofurane^acetate: 9. Co:i3pound 8 (67 g), anhydrous 1,2-dichloroetlaane (250 ml), andp-anisoyl chloride (59.55 j^) were added in a 1,000-ml flask undea- inert atmosphere. The solution was cooled in an ice bath, and SnCl4 (115 ml) was addtjd slowly. The bath was allowed to warm up to 25'C and the solution was then stiiTcd for another 24 hours. The solution was poured into an ice/water mixture (1,000 ml). The organic phase was collected, washed with 3% sodium bicarbonate (2 x 500 ml) and with water (500 ml), and then dried over magnesium sulfate. The solvent was evaj)orated. The oily residue was stirred for 24 hours into hexane (100 ml). The product is a pale yellow powder. The yield was approximate!)^ 103.3 g. 2-C3-p-hvdTQyvfaenzovIben2Qfiirane^acetic acid: 10. Aluminum powder (45 g), benzene (900 ml), and iodme crystals (345 g) were introduced in a 2-liter flask with efBcient reflux condenser and mechanical stirrer. Tne solution was placed in a water bath and stirred until most of the heat had dissipated, then stirred at reflux temperature until the red color of iodine disappeared (approx. 30 minutes).. This mixture was cooled to 25'C tiien, while stirring, compound 9 (70 g) and tetrabutylammonium iodide (0.86 g) * wei'B added. When addition was complete, a portion of the solvent (600 ml) was distilled away, then the remaming solution was cooled to 25 ^'C- A portion of ice-water (700 ml) was slowly added, followed by ethyl acetate (600 ml). The resulting suspension was filten^d and the residue washed with more ethyl acetate (2 x 50 ml). The organic phase was washed with more water (500 ml), then extracted with 3% sodium bicarbonate (3 x 1,200 ml). The combined aqueous phases were washed with ethyl acetate (200 ml). The aqueotjs solution was placed into an ice bath and ethyl acetate (250 ml) was added. The solution was acidified slowly using 6 N HCl while stirring. The organic phase was washed with water (200 ml), dried over magnesium sulfate, filtei:e4 and the solvent evaporated. The yield was approximately 26 g. 2^343S'Aiiod£^-A-hvdTQX^Mmmvm acid: 11, Compound 10 (25.25 g) was dissolved in water (250 ml) containing potassium carbonate (23,85 g). Iodine (47.57 g) was added and the mixture was stirred at 25 ""C for 90 minutes. Two hundred milliliters of water was added and the solution acidified with 2 N HCl The residue was filtered, then dissolved in ethyl acetate (500 ml), washed with water (500 ml), then with 5% sodium liiioaulfete (2 x 500 ml), then with water (500 ml). Theresidue was dried over magnesium sulfate, and the yield was approximately 37 g. Methvl.2-[3-f3.5-diiodo^hv(^oxvben2ovl>benzQfiirane]acetate: 12. Compound 11 (16.4 g) was dissolved into methanol (100 ml) and concentrated sulfuric acid (1 ml). Tht; solution was refluxed for 1 hour, Hhm the solvent was evaporated. The residue was dissolved in ethyl acetate (500 ml) and washed with 5% sodium bicarbonate (300 ml). Extraction was done with 0.15 N NaOH (3 x 150 ml). The solution was acidified with 6 N HCl and extracted with ethyl acetate (2 x 150 ml), ^lat^^o^-ganic phase was washed wii 1% sodium bicarbonate (2 x 300 ml) and dried over magnesium sul^^TIic:::^'ield was approximately 11.64 g. Methyl 2-f3'r3.5-diiodor4-diethvlaminQethQxvben2ovnben2Qfurane]acetate: A. Compound 12 (2.88 g) was dissolved in 0.1 N NaOH solution (51 ml). Methylene chloride (25 ml) is added. Benzyltrietbylammonium chloride (0.114 g) and a solution of diethylaminoetfayl chloride (0^96 g) in methylene chloride (25 ml) was then added. This was stirred for 2 hours at 25 C. The organic phase was washed with 0,1 N NaOH (50 ml). 1N HCl (50 ml), 0.1 N NaOH (50 ml), and water (50 ml) and dried over magaesium sulfate to yield the subject compoimd. pxaigple g - Alternative Synthetic Route for the Novel Compounds An alternative synthetic scheme is shown in Figuj-e 2, whore 2-bmzofurane acetic acid, compoimd %> can be made by an alternative reiiction that involves synthesizing 2-acetyibenzoftiran 13 from salicylaldehyde 1 reacted wii chloroacetone, followed by a chair, elongation procedure known as fee Willgerodt-Kindler reaction in order to make the tl:domoipholide derivative 14 which is then hydrolyzed to compound 7. The remainder of the syntbdic scheme to the novel compound A is ihsn. essentially identical to Example 1. 1. Acerulbenzofuran \|3. Salicylaldehyde (326/7 g) is introduced into a 3-liter 3-necked round-bottomed flask containing potassium carbonate (415 g) and acerone (500 ml). ChloToacetone (252,6 g) is then added dropwis;es v/hile stilting, over a period of 30 minutes, followed by addition of another portion of ai^etone (500 ml). The mixture is stirrsd at reflux temperature for 4 hours then cooled to 25 °C and filtered. The filtrate is eva]>orated and gives approximately 441 g of a red crystalline solid, 2-acetylbenzofuran li, which is pure enough for step 2, below. To verify the identity of the product, a small porion was distilled in vacuo (P - 0 J mm Hg) using a short path distillation apparatus, and it was detennined that the pure product distills at 80'C, yielding a white crystalline solid. 2. Benzofarane acetic acid 7. The crude 2-acetylbenzoforan H (441 g) is dissolved in morpholine (25635 g) in a 3-liter 3-necked round-bottomed flask. Sulfur (~ 90 g) is added, and the mixture is stirred at reflux temperature (108 "* C) for 120 minutes. This reaction yields the intermediate thiomopholide derivative H. The mixture is cooled to 25 T. Methanol (750 m\\ water (500 ml), and sodium hydroxide (220 g) ai-e added, and the mixture is stirred at reflux temperature (80 ^^C) for another 4 hours. A portion of the solvent (750 ml) is then removed by distillation. The volume of the solution is brought to 6 liters wife water. NaOH (40 g) and activated decolorizing charcoal (5 g) are added and fee mixture is stirred at reflux temperature for 60 minutes, feen filtered through celite. The mixture is then acidified to pH 2 with 12 N HCl, md the product is extracted with ethyl acetate. The extract is dried over sodiimi sulfate and evaporated, yielding appro3(imate]y 289 g of a dark solid. The crude product can be used for the next step without further purification. All physical properties of this product arc identical to compc»und Z and can be used in an identical manner afi compound 1 in the synthesis scheme described in Example 1, above. Example 3 -Partition Coefficient of Novel Compounds The thermodynamic properties of the new compound A can be evaluated by measuring its pardtion coefficient, P, between a pH 7.4 phosphate buffer and octanol. The buffer solution and octanol are mutually saturated before the experiment The test compounds can be dissolved in the octanohbuffer mixture at such a concentration that neithcir phase is saturated. The volume ratio between buffer and octanol is adjusted so that tlie concentration of compound in water after equilibrium is measurable. The n:iixture is shiiken for I hour and centrifuged in order to obtain complete separation of the two phas(5S. The concentration of test compound can be measured in the aqueous phase before and after equilibrium^ using a UV detection method. The partition coefBcient can be calculated using the following equation: where P is the partition coefScientj and C^ and C^ are the concentrations of test compounds in octanol and in water, respectively. Since measurements take place only in aqueous buffer> the equation has to be modified to the following, which can be used in this expe:riment: where Q^ is the initial amount of test compound introduced in the buffer;octanoi mixture, Q^ is the amount of test compound in buffer phase after equilibrium has been reached, and V^, iind V(^ are the volumes of buffer and octanol, respectively. Example 4 - Stability m Buffer and Metabolism Rate in Human Plasma Analytical method. Standard HPLC techniques can be used to determine the concentration of the drag in buffer and in human plasma using standard analytical procedures known in the art. Stability in buffer, A known concentration of the novel compound A can be incubated in a pH 7,4 phosphate buffer at 37 "C, AUquots of the solution can be taken at various recorded intervals and diluted to the appropriate concentration for injection into the HPLC system. The hydrolysis rate constant, K^ in buffer can be calculated from the plot of drug concentration vs. time. ls4et^bQlism rate in humai\ plasma. The same procedure as above can be used with humen plasma instead of buffer* The rate constant in plasma can be compared to the rate constant in buffer in order to give an ^proximated rale of metabolism by plasma enzymes. Example 5 - Elftctronfavsiological Properties in Gumea Pig Heart Antiarrhythmic activity in guinea pig heart prepaj-ations can be tested for the novel comi)ound A by methods and techniques well know3a by those of ordinary skill in the art. Anti;arrhythmic activity in guinea pig heart preparations is accepted in the art as a model for ;mtiarrhythmic activity in humans. Specifically, activity in guinea pig heart preparations is used to show that a compound depresses the spontaneous discharge, slows the s:inus node spontaneous firing rate, prolongs the effective refractory period (ERP), slows the intra-atrial conduction, suppresses atrial premature beats, prolongs the ventricular ERP, and decreases ventricular excitabili.ty. Microelectrode and pacing techniques can be used as are standard in the art. Assays to show such activity can be conducted in the isolated, superfused guinea pig S-A node-right atrial preparation. A ^11 dose-response curve for compound A can be calculated in each preparation in order to denrtonstrate the effects of different doses on S-A node spontaneous rate, atrial action potratial duration (APD) and ERP, and on ventricukir APD and ERP. The EG50 (the effective concentration that produces 50% of the maximum response), as well as the threshold and maximum doses for the compound can be determined from the full dose-response curve- The results of electrophysiological studies carried out in guinea pig isolated hearts using the subject compound, compound A, showed that compound A displays electrophysiological properties classically associated with Class HI antiarrhythmic agents. The results of these studies are shown in Figures 3-5. Compared to the known compound, aimodarone, tiie electrophysical effects of the subject compound show several advantages. For example* on an equimolar basis, the electrophysiological effects of compound A on atrioventricular conduction, intraventricular conductirA and ventricular repolarization times are much greater than those of aKiiod-arone, both in the spontaneously beating heart (see Figures 3A, 3C, and 3D), and in tlie paced heart (see Figures 4A, 4C, and 4D). In addition, the effects of compound A on atrioventricular conduction, intraventricular conduction and ventricular repolarization times can be partially reversed upon discontinuation of the drug, whereas the effects of iuniodarone are not reversed and acmaliy tend to continue to increase even after discontinuation of the drug. Compound A is also able to more selectively increase the time of ventricular repolarization (i,e., prolctng the QT interval) relative to the changes obsen/ed on sinoatrial nodal rate and baseline atrioventricular nodal conduction time, as compared to amiodarone (Figures 3A-. 3D). Specifically, Figures 3 A-3D show the time-dependent electrophysiological effects of a continuous 90-niinute infusion of compound A (1 jiM, n=3), amiodarone (1 ^M, n=3) and vehicle (control, n=3) on the spontaneously beatmg heart. Changes from baseline vaiues of atrial rate (Figure 3 A), A-V interval (:?igure 3B), QRS interval (Figure 3C) and QT interval (Figure 3D), respectively, are plotted as a fimction of time. Figure 3 A shows thatj compared to control hearts^ compound A and amiodarone caused significant time-dependeat reductions in atrial rate of similar magnitude. In contrast, compound A and amiodarone caused only a small prolongation of the A-V interval (Figiure 3B). The minimal effect of compound A and amiodarone on atrioventricular nodal conduction in spontaneously beating hearts can be at least partly explained by noting that atrial rate modulates the effects of drugs on atrioventricular nodal conduction. That is, concomitant slowing of atrial rate will lessen the depressant effects of drugs on atrioventricular nodal conduction. For example, in paced hearts where atrial rate is kept constsnt, compound A (1 \|iM) had a much greater effect on atrioventricular nodal conduction (Figure 4A). Unlike the effects of amiodarone^ the actions of compound A on A-V interval were reversed upon discontinuation of the drug iniusion, hereafter referred to as washout (Figure 3B). In addition, compound A but not amiodarone signifcantly prolonged tlie QRS interval, i.e., slowed intraventricular conduction (Figure 3C). During the 90-minute washout period of compound A, this effect of compound A was completely reversed. Likewise, although compound A and amiodarone significantly incre£.sed the QT interval^ the effect of compound A to prolong tlie time for ventricular repolJJrization was much greater (Figure 3D). Whereas the effect of compound A on repoliirization was partially reversed during washout, Ihe effect of amiodarone was not attenuated during washout. The average baseline valties of atrial rate, A-V interval, QRS interval and QT interval were 204.6±2.4,55.0±4.0,21,2±0.8 and 162,5±2.9, respectively. Data are shown as meaniSEM, Figures 4A-4D show a series of separate experiments, the time-dependent electi'Ophysiological efifects of a continuous 90-minute iJifusion of compound A (1 pM, n=3): amiodarone (1 jiM, n=3) and vehicle (control, n=3) in guinea pig hearts paced at 200 beats per minute was investigated. Changes from baseline values of S-H interval (Figure 4A), HV interval (Figure 46), QRS interval (Figure 4C) and QT interval (Figure 4D), respectively, are plotted as a function of time. At equimolar concentrations, com]:)ound A d^ressed atrioventricular nodal conduction in paced hearts to a much greater extent than amiodarone (Figure 4A). The prolongation of the S-H interval caused by compound A was gradual and reached a maximum of 18 msec (i.e., a 45% increase above the baseline S-H interval) before the drug infusion was stopped. Upon washout of compound A, a large fraction (» 70%) of this effect was reversed. In contrast, amiodarone had no effect on S-H interval during the period of drug infusion* Compound A and amiodarone had no effect on His-Purkinje conduction times, i.e., the HV interval remained constant (Figure 4B). Similar to its effects on S-H inteival, compound A but not amiodarone prolonged intraventricular conduc>tion time, i.e,, increased the QRS intei-val (Figure 4C). The increase in QRS interval was gradual and reached a maximum of 1.3.5 msec (60% increase above baseline value) befo3e the dmg infusion was disconiinued. The effect of compound A on intraventricular conduction was completely reversed dijrmg the 90-mmute washout period. Compoimd A and amiodarone both significantly increased the QT interval. However, compoimd A was much more potent at prolonging the time for ventricular repolarization than was amiodarone CFigure 4D), Wheresas the effect of compound A on repolarization was partially reversed during washcut, the effect of amiodarone was not attenuated during washout The average baseliie values of S-H interval, AV interval, QRS interval and QT interval were 40. l=fcl .9 msec, 7,Si:0.6 msec, 223±0.7 msec, and 164.0±1,7 msec, respectively. Data are shown as meaniSEM. Figure 5 shows a comparison of the electrophysiological actions of an equipotent (to prolong the baseline S-H interval) concentration of arcdodarone to those effects found using 1 ^M compound A. For this purpose, a concentration of 5 ]xM amiodarone was seleci:ed. Whereas amiodarone (5 ,\|iM) caused a time-dependent increase in S-Hj QRS and (JT intervals, it had no effect on the HV interval Of the intervals measured, amiodarone (5 jj.M) had the greatest effect on atriovtsntricular conduction time. It prolonged the baseline S-H interval by 74 msec at 90 min of drag infusion before ihe heart went into second degree AV block. This large prolongation of S-H interval was accompanied by only a 20 msec increase in the QT intenral. On the oth^ hand, although com]30und A (1 \|.iM) caused an increase of 18 msec in the baseline S-H interval at 90-min of diug treatment (Figure 3A), it was accompanied by m increase in the QT interval of 28 msec (Figure 3D). Thus, compound A, compared to amiodarone, is able to more selectively prolong the time for ventricular repolarization without causing as much depression of atrioventricular nodal conduction. Likewise, as shown in Figure 3 A, at corcparable degrees of atrial rate slowing, compound A was able to produce a much greater increase in the QT interval ia spontaneously beating hearts (Figure 3D). Taken tog One of the major drawbacks of amiodarone in the clinical setting is its long half-life (> 30 days), which can cause severe life-threatening side effects that are slow to resolve even after discontinuation of drug therapy. The advantages of compound A over amiodarone or other currently used antiarrhythmics are that it exhibits more selective antiarrhythmic action, has a potentially shorter half-iifcj aid has cardiac effects which are more easily reversed ('washed") upon cessation of drug treatment. Exairtple 6 - Exemplary Synthetic Pathway for Productiop of Compounds (m^2) The following is an exemplary pathway for the synthesis of compounds of the subject invention wherein m=2 and Zj and Z^ are both iodine. Stepl: Synthesis of 2-benzofurapvl ethvloyvcarboD\Imetbvl ketone m 122g of salicylaldehyde 1 and 350g of potassium carbonate are dissolved in 2L of acetone. While stining at room temperature, aiid slowly 165g of ethyl 4-chloroacetoacetate 2 over a period of 2 hours. Wh^sn addition is over, stir at reflux for another 4 hours. Cool to room temperature and filtei:. Wash the filtration cake with 0.5L ofaiietone. Evaporate the solvent Step 2: Synthesis of ethvl benzofuy-ane-l-propionate (4232g of compound 3 are dissolved in SOOml of €:thanoL Cool in ice-bath and add lOOg of sodium horohydride in SOOml of water. Stir for 2 hours. Add acetic acid until the sodium borohydride has been neutralized. Cool the solution in ice-bath under an atmosphere of nitrogen and add lOg of 10% Pd/C catalyst. Stir under a hydrogen atmosphere at 15PSI until the reaction is complete, as judged by TLC. Filter through celite and evaporate organic solvents. Extract with ethyl acetate. Dry over sodium sulfate. Filter, Evaporate solvent. step 3: Synthesis of ethvl 3-r3,5>(iiiodo-4-b vdroyvbeiizovnbeDzofurape-2^proDionate IS) 21Sg of compound 4 aiid 409g of S^S-diiodo-^-hydroxybettzoyl diloride are dissolved in 2L of anhydrous nietbylene chloride. Slowly add 287g of tin(IV) chloride. Stir at room temperature for 12 hours and pour into 3L of ice-water. Wash the organic phase with 5% sodium bicarbonate solution and then with 2N HCl. Diy over sodium sulfate. Evaporate. The product is crystallized from ethianol. iStep 4: Synthesis of f3>S-diiodD^-hvdrQXvbenzov]^ben2Dfurane-2propionic acid {€300g of compound S are dissolved in 200ml of acetic acid and 300ml of 12N HCl. Stir at 90°C for 2 hours and distill at least 400ml of solvisnt. Cool to room temperature and add IL of water. Stir well for 2 hours and filter. Wash with water. Diy. Step 5: Svnthe&is of ggc^-butyl 3-f3>S-diiodo>4 hvdrQyvbenzQv!>benzofuraDe-2- propijoff^ttp (7) 562g of compound 6 are stirred at 85^C in 900g of 2-butanol and 50ml of sulfijiic acid lor 5 hours. Cool down to room temperature. Filte:r the product. Wash twice \vith 100ml of hexane. Step 6: Synthesis of ^^g^butvl 3^f3.S-di\|odo-^t-diethv]qniipoetboyvben2ftvn ben?:ofaraqe>;i-prppionat^ (8) 619g of compound 7 and ISOg of diethylaminoethyl chloride, hydrochloride salt, are dissolved in 2L of methylene chloride and 500ml of water. To this add 23g of beniyltriethylammonium chloride and SOg of sodium hydroxide in 2L of water. Stir vigCTously for 5 hours. Keep the organic phase. Wash with IL of water. Dry over sodium sulfate. Filter. Evaporate. Eicaini>le of salt: hydrochloride Kalt 700g of compound and IL of IN HCl are stirred for 2 hours. The product is filtered dry and is stirred again in 200ml of water and 2L of methyl re^'-butyi ether contauiinglOg of sodium chloride. The organic phase is dried over sodium sulfate. Filter. Evaporate the solvent gyan^ple 7 - Uses. FormulatinTis, and AdTniniRtrations Therapeutic and prophylactic application of the subject compounds, and compositions comprising them, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. Further, the compounds of the invention have use as starting materials or intermediates for the preparation of other useft.l compounds and compositions. The compounds of the invention arc useful for various non-th^apeutic and therapeutic purposes. It is a]:>parent fix>m the testing that the compounds of the invention have effective antiarrhythmic activity. Specifically, they m:e useftil in regulating cardiac anhythmia, including atrial fibrillation, in animals and humans. The administration of the subject compounds of the invention is useful as an antiajbythmic agent Thus, pharmaceutical compositions containing compounds of the invention as active ingredients are useful in prophylactic or therapeutic treatment of cardiac arrhythmias in humans or other mammals. The dosage adnunistered will be dependent upon tiie response desired; the type of host involved; its age, health, weight, kind of concurrent treatment, if any; fi^equency of trtatment; therapeutic ratio and like considerations.. Advantageously, dosage levels of the aininistered active ingredients can be^ for examples, dermal, 1 to about 500 mg/kg; orally, 0.01 to 200 mg/kg; intranasal 0.01 to about 100 lEg/kg; and aerosol 0.01 to about 50 mg/kg of animal body weight Expressed in terms of concenrration, the actii^e ir.gredient of the invention can be presesnt in the new compositions for use demaally, intranasally, bronchially^ mtrajnuscularly, intravaginally, intravenously, or orally hi a concentration of from about 0.01 to about 50% w/w of the composition, and especially from about 04 to about 30% w/w of the composition. Preferably, tiie novel compo^ond is present in a composition from about 1 to about 10% and, most preferably, the novel composition comprises about 5% novel compound. The compositions of the invention are advantageously used in a variety of forms, e.g., tablets, ointments, capsules, pills, powders, aerosols, granules, and oral solutions or susp'3nsions and the like containing the indicated suitable quantities of the active ingredient. Such compositions are referred to herein and in the accompanying claims C laims 1. A compound having the structure wherein R - H, OH, KH^^ SH, hnlide, aik)'l, O-alicj'l, acyl, 0-acyl, ijryl 0-aryl, substituted amine* or substituted ttdol; y - OR,j wherein R^ is a straight or branched cluiin alir/I or heterc^aikyl having 1 to {\ carbon atoms, a substituted or unsubsututed ajyl or heteroaryl; or wherein R^ and R^ are independently selected from K, alky] or heteroaliryl of 1 to 6 carbon aioms^ or w^heiein N is part of a cyclic or hciterocycUc group compnsing morjihohnfij triazole, zdlty p>'nolidine, piperidine, piperazine, p^irole, dihydrop>Tidinej aziridine, thia2oUdine, thia^oline, thisdia^olidine, or tliiadiazoliiie/ wherein Zj and Zj are selected from the group consisting of fluorine, broniine, and chlorine; and X is O, S, orNH; a derivative of said compound; or a salt of said compound 2. The cotnpoimd, according to claim 1, wherein R is H and X is O, 3. The compoxmd. according to claim 1, where^in the salt of said compound is selected from the group consisting of hydrobromide, hydrachlaride, malate, p- toluenesulfonate, phosphate, sulfate, psrchlorate, acetate, trifluororacstats. proprionate, citrate, malonate, succinate, lactate, tartrate, benznate, raorpholine, pipericline, dimethylamins, and diethylaminc? salts. 4. The compound, according to claim 3, whtireiii the salt of said compound k a sulfate: salt. 5. A phaimaceulical composition for treating cardiac arrhytlmiia in an animal wherein said pharmaceudcal composition comprises a compound having the stracmrs t i wherein K = H. OH, NH^, SH, halide,, aiicyl, 0-s.liryl, acyl 0-acyl, aryl, 0-ar/], substituted amine, or substituted thiol; Y ^ ORp whersiin R, is a straight or branched cliain alkyl or heteroalirv'l ha\iag 1 to i carbon atoms, a substituted or unsubstituied £iryl or heteroaiyi; or wherein Rj and R3 are independently selected fiom H, alkyl or hete^roalkyl of l to 6 carbon atoms, or wherein N is part of a cyclic ox heterocyclic group comprising moTjiholine, triazole, imidazole, pyix-olidine, piperidine, piperazine, pyrrole, dihydropyridine, azhidine, thiazolidtae, thiazoline, thisdiazolidine, or thiadia2oiin£; wbeiein Z, and Z, are selecte;d &om the group consisting of fluorine, bromine, aad chlorine; and > X is 0, S, or NH; a derivative of said compound; or a saJi of said compound. 6. The phannaceurical coinpoiitiou> according tc» claim 5, wherein R is H. 7. The pharmarseutical coraposiiion, according to claim 5, wherein the sail of said compouad is selected from the gi'oup consisting of hydrobromide, p- TolueDesuifonatt, hydrochloride, malate, phosphate, sulfate, perchJorate, acetate, triflucroraceiate, proprionaie, citrattj malonate, succinxits, lactate, tartraie, benzoate, morprioline, piperidine, dimethylaniins. and diethyla-mine salts. 8. The pharmac;iuti'cal coniposition, accorduig to claim 7, wherein the salt of said compoimd is a sulfate salt. 9. The pharmaceutical composition, according to claim 5, whersm said pharnacemical composition comprises about 0.01% lo about 50% of said compound. * 10. The pharmaceutical composition, accor^^ing to claim 5, wherein said comf osition comprises from about 0.1% to about 30% of said compound. 11. The pharmaceutical composiiioa, according; to ciaiui 5, wherein said phannaceudcal compodtion comprisies from about 1% to about 10% of said conii)ound. 12. A method for treating cardiac anhythmia in an aniniai, wherein said method comprises administering an effeciive amount of a compound having tlis wher£:m R =^ H, OH, NK2, SH, balide, atkyl, 0-aIl:y!, acyl, 0-acyl, aiyl, 0-ar>'l substituted amine, or substimted thiol; Y = ORj, where:j} Rj is a straight or branched cliain al5Ql or hetsroalk^^ having I to S carbon atoms, a substituted or uusubstituted aryl or heteroaryl; or wherein It^ and R3 are independently selected firom H, alk>^I or heteroaUcyl of 1 to 6 c;arbon atoms, or wherein N is part of a cyclic or httterocyclic group comprising morpholine, triazole, imidazole, pyiroHdine, piperidine, piperazine, pyixole, dihViiropyridine, aziridine, thiazolidine, thia:2oIine, thiadiazolidine, or ihiadiazoline; wherein Z^ and 2^ are selected from the group consisting of fluorine, bromiiie, and iihlorine; and X is O, S, or Nli; a derivative of said conipound; or a salt of said compound. 13. The method, according lo claim 12, wherein R is H and X is O. 14, The method, according to claim 12j wherein said composition is adn^inistered to a mananal. 13. The method, according 10 claim 14> wherein said composition is adn'iinisteTed to a human. 16. The method, according to claim 12, v/herein said composition is administered in combination with a second pharmaceutical composition. wherein R = H, OH, NH,, SH, halide, aUcyl 0-alkyl, acyl, 0-acyI, aryl, 0-aryl, substituted amine, or substituted thiol; y = ORj, wherein Rj is a straight or branched chain alkyl or heteroalkyl having 1 to S carbon atoms, a substituted or unsubstituted aryl or heteroaryl; or wherein R^ and R3 axe independently selected firom H, alkyl or heteroalkyl of 1 to 6 carbon atoms, or wherein N is part of a cychc or hstsrocyclic group comprising morDholine, triazolCj imidazole, pyrrolidine, piperidin:;, piperazine, pyrrole, dihydropyridxnej aziridine, thiazolidine, thiazoline, thiadiazolidine, or thiadiazohne; wherein Zj and 7^ are iodine; XisO, S,orNH;and wherein said salt is selected from the group cor.sisting of hydrobromide, p-toiuenesulfonate, phosphate, sulfate, perchlorate, ai^etate, trifluororacetate, propirionate, citrate, malonate, succinate, lactate^ ta:rtrate, bensoate, morpholinej piperidine, dimethylamine, and diethylamine salts. IS. The compound, according to claim 17, whtirein R is H and X is O. 19. The compound, according to claim 17, wherein the salt of said compound is a sulfate salt, 20. A compound having the structure wherein Zj and Z^ may be the same, or diffexent, and are selected from the grou]3 consisting of iodine, fluorine, bromine, and chlorine and X is 0, S, or NH; m has a value fi-om 0-10; R = H, OH, KTH^, SH, haiide, alkyl, O^alkyl, acyl. 0-acyl, aryl, 0-aryl, subsiituted amine, or substituted thiol; Y - OR,, whensin R, is a straight or branched chain alkyl or hetero alkyl having 1 to 8 carbon atoms, a substituted or unsubstituted aryl or heteroaryl, or R. "R3 wherein R2, and R^ are independently selected from H, alkyl or heteroalkyl of 1 to 6 atoms; or wherein m has a value fi-om 0-10; Rj is a moiety selected from the group consistiag of C„.JQ alkyl, Cj,,^o hetexoalkyl, C2_2o aUcenyl, aryl, C^^oo alkyl-aryl, C^.^^. alkenyl-aryl, heteroaryl, Cj^jo alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C^.^^ alkyl-hetei'oycloalkyl, and Ci.2p alkyl-cycloalkyl, any of v/liicb maybe substituted with a moiety selected from the group consisting of C^^^ alkyl, halogen, CN, NO^, and SO^; Rj and R3 may be the same or different and are selected from the group consisting of C^2o alkyl, C^^^o heteroalkyl, C^.jo allcenyl, a:ryl, C1.20 alkyl-aryl, C^so alkenyl-aryl, heteroaryl, C1.20 alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloaUcyl, heterocjycloalkyl C^.io alkyl-heteroycloalkyl, and C^^2o ali:yl-cycloalkyl, any of which may be;, optionally, substituted with a moiety selected frcm the group consisting of Cj,^^ alkyl, lialogen, CN, NO^, and SOa^; n is one; or wherein N is part of a cyclic or heterocyclic group selected from the group consisdng of morpholine, triazole, imidazole, pyrrolidine, piperidinej piperazine, pyrrolij, dihydropyridine, aziridine, thiazolidine, thia:ioliae, tbiadiazoHdine, or thiadifizoline. 21. The compound, according to claim 20, AA'herein the salt of said compound is selected from the group consisting of hydrobromide, hydrochloride, malate, p- toluer.esulfonate, phosphate, sulfate^ perchlorate, acetat€i> trifluororacetate, proprionate, citrate, malonate, succinates lactate, tartrate, benzoate, morpholine, piperidine, dimethylamine, or diethylaniine salts, 22. The compoimd, according to claim 21, v^herein the salt of said compoxmd is a sulfate salt. 23. A pharmacejutical composition for treating cardiac arrhythmia in an animal wherein said pharmaceutical composition comprises a compound having the structure wherein Z^ and Zj may be the same, or different, and are selected from the group consisting of iodine, fluorine, bromine, and chlorine and X is O, S. or NH; m has a value from 0-10; wherein R = H, OH, NH^, SH, halide, alkyl, 0-all7l, acyl, 0-acyl, aryl» 0-aryl, substi'tuted amine, or substituted thiol; Y - ORi, wherein R^ is a straight or branched chain alkyl or hetero alkyl having 1 to 8 carbon atoms, a. substituted or unsubstituted aryl o:' heteroaryl, or whei'cin Rj? ^^ ^^3 are independently selected from H, alkyl or heteroalkyl of 1 to 6 atoms; or wherein m has a value from 0-10; R^ is a moiety selected from the group consisting of C^^^jo alkyl, C^.^o heteroalkyl, Cj.20 alkenyl, aryl, Cj.20 aJkyl-aryl, Cj.jo alkenyl-aryl, beteroaryl. Ci,2o ^^^ heteroaryl, C2.20 alkenyl-heteroarylj cycloalkyl, heterocycloalkyl, C1.20 allcyl-heteroycloalkyl, and C^^jo alkyl-cycloalkyl, any of wliich maybe, optionally, substituted with a group selected from the group consisting of C^,^ alkyl, halogen, CN, NO., and Ro and R3 maybe the same or different and £ire selected from the group consisting of C^,2o alkyl, C„.2o heteroalkyl. C2.20 alkenyl, aryl, C,.2o alkyl-aryl, Cs.io alkenyl-aiyl, heteroaryl, C^^^o alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C^^^o alkyl-heteroycloaikyl, and Cj,2o alkyl-cycloalkyl, any of which may l^e^ optionally, substituted with a moiety selected firom the group consisting of Cj.^ alkyl halogen, CN, NO2, and SOj^; n is one; or wherein N is part of a cyclic or heterocyclic gjoup selected from the group consisting of morphoHne, triazole, imidazole, pyrrolidine, piperidine', piperazine, pyrrctle, dihydropyridine. aziiidine, tbiazolidine, tbiazoline, thiadiazolidinej or thiadiazoline. 24. The pharmaceutical composition, accordtag to claim 23, whereiu R is H. 25. The pharmaceutical composition, according to claim 23, wherein the salt of said, compound is selected from the group consisti^ig of hydrobromide, malate, hydrocihloride, p-toluenesulfonate, phosphate, sul&te perchlorate, acetate, trifluororacetatej proprionate, citrate, malonate, succinatti, lactate, tartrate, and benzoiite, morpholine, piperidine, dimetbylaminej ordielhylaniiiie salts, 26. The pharmaceutical composition, accordmg to claim 25, wherein the sal: of said compound is a sulfate salt, 27. The pharmaceutical composition, according to claim 23, wherein said pharmaceutical composition comprises about 0.01% to about 50% of said compound. 28. The phamiaceutical composition, according to claim 23, wherein said composition comprises from about 0.1% to about 3C'% of said compound. 29. The pharmaceutical composition, according to claim 23, wherein said pbarraaceutical composition comprises from about 1% to abom 10% of said w comp'ound. 30. A method for treating cardiac arrhythmia in an animal, wherein said wherem Zj a^d Zj may be the same, or different, :and are a halogen selected from the group consisting of iodine, fluorine, bromine, a:id chlorine and X is 0, S, or NH; m has a value from 0-10; wherein R = H, OH, NH., SH, haiide, alkyl, 0-aIlcyi, acyl, 0-acyl, aryl, O-aryl, substituted amine, or substituted thiol; Y = OR3, whereii R, is a straight or branched chain allcyl or hetero aD^'l having 1 to 8 carbon atoms, a substituted or unsubstituted aryl 01 heteroaryl, or wherein Rj, and R3 are indepeixdently selected from H, alkyl or heteroalkyl of 1 to 6 atoms; or wherein m has a value from 0-10; R^ is a moiet}' selected from the group consisting of Cr,.2o ^^l Cn-20 heteroalkyl, C2.20 alkenyl, aryl, C].2o alkyl-aryl, C.^o alkenyl-aiyl, heteroaiyl, Cj^o alkyl-heleroaryl, C^jo alkenyl-heteroaryl, cj^cloalkyl, heterocycloalkyl, C^^o aBcyl-heteroycloallcyl, and Cj^jo alkyl-cycloallcyl, any of wliich maybe, optionally, substituted with a group selected from the group consisthig of Cj^ ^Jkyl, halogen, CN, NO^, and R2 and R3 may be the same or different and are selected from the group consisting of Cn^o alkyl, C^.^^ heteroalkyl, 62.^0 alkeryl, aryl, C).2o alk^l-aiyl, €2,20 alkenyl-aryl, heteroaryl, Cj^^ alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C, ^p alkyl-heteroycloalkyl, and C^.20 alkyl-cycloalkyl, any of which may l)e, optionally, substituted with a moiety selected fi-om the group consisting of Cj.^ alkyl, halogen, CN, NO., and SO^^; n is one; or wherein N is paxt of a cyclic or heterocyclic group selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine. pyrrole^ dihydropyridxne, aziridine, tbiazolidine, lhia2oIinep thiadiazolidine, and thiadiazoline. 31. The method, according to claim 30, wherein R is H and X is O. 32. The method, according to claim 30, wherein said composition is administered to a mammal. 33. The method, according to claim 30> wherein said composition is administered to a human. 34. The method^ according to claim 30, wherein said composition is administered in combination with a second pharmaceutical composition. A compound substantially as herein described with reference to the accompanying drawings. A pharmaceutical composition substantially as herein described with reference to the accompanying drawings.

Full Text

PESCMPTJQN
NOVEL COMPOT JNDS FOR TREATMENT OF C^^RDIAC A3^T?HYTHMIA.
SV>JTHRSIS. AND METHODS OF USE
Cross-Reference to Rftlated Applications This application is a contmuation-in-pait of co«pendiBg application Serial No. 09/211,246, filed December 14, 1998; which is a ciivisdon of application Serial No. 08/465,602, filed June 6,1995» now U.S. Patent No. 5,849,788; which is a division of application Serial No. OS/260,869, filed June 16,1994, IK>W U.S. Patent No, 5,440,054; which is a continuation-in-part of application Serial No. 08/078,371., filed June 16,1993, now U.S. Patent No. 5,364,880.
Background of the Invention
Congestive heart failure (CHF) is a disease aiifecting approximately 2% of the population of the United States (Sanii, M.H. [1991] 1 Clin, Pharmacol 31:1081). Despite advances in the diagnosis and treatment of CHF, tlae prognosis remains poor with a 5-yesar mortality rate higher tiian 50% fi^m the time of diagnosis (McFate Smith, W. [1985] Am. J. Cardiol 55:3A; McKee, P.A., W-P. Castelli, P.M, McNamara, W,B. Kannel [1971] K Engl 1 Med, 285:1441). In patients willi CHF, the rate of survival is lowest in those patients wifh severe depression of left ventricular function and patients who have fi-equent ventricular arrhythmias. Patients with ventricular arrhythmias and ischemic cardiomyopatiiy have an increased risk of sudden death. The presence of ventr].cular tachycardia in patients with severe CHF resiilts in a three-fold increase in sudden death compared to those without tachycardia C-Bigger, J.T., Jr. [1987] Circulation 75(supplIV):28). Because of the high prevalence of suddsn unexpected death in patients with (^HF, there has been a growing interest in the prognostic significance of arrhythmias in these patients.
Several compounds have been used in the management of cardiac anrhythniias in patients with congestive heart failure. Unfortunately, antiarrhyttunic dmg therapy has

been disappointing. The efficacy of antiarrhythmic cbiigs markedly decreases as left ventricular function declioies, such that only a small fraction of patients with CHF are responsive to autiairhythxnic therapy. No antiarrhythmic drug has prevrated sudden death in patients with CHF. There is even a question of increased mortality associated with certain antiarrhythmic drugs (the CAST investigators [1989] N, Engl 1 Med, 321:406). Scientists define tachycardia and ventricular fibrillation as being of multiple nature. It now seems clear, and is accepted in the art> that re-entry is the underlying mechanism to mt:>st sustained arrhythmias. Prolonging ventricular repolarization as a means of preventing ventricular arrhythmias has consequently received renewed attention. This pointis to Class-m agents as drugs of choice in the treatment of arrhythmias. A Class-IE agentj as referred to herein, is an agent which is classified as such in the Vaughan-Williams classification of antiarrhythmic drugs. A Class-HI agent exerts its primary antiatihythmic activity by prolonging cardiac action potential dxiration (APD), and thereby
the effective refractory period (ERP), with no e:Sect on conduction. These
•
electrophysiological changes, which are brou^t about by blockade of cardiac potassium chamiels, are well known in the art. Because the blockade of cardiac potassium channels is not associated with depression of the contractile function of the heart, Class-HI agents are pjirticularly attractive for use in patients with CHE'. Unfortunately, the existing Class-Hi agaits are limited in their utihty by additional phaima^:ological activities, lack of good oral bioavailability^ or a poor toxicity profile. The only two Class DI agents currently marketed are bretylium (i.v. only) and amiodarone (i.v. and p.o.).
Amiodarone is an antiarrhythmic agent having vasodilator properties that may beneiit patients with severe heart failure. Amiodarone has been shown to improve survival of post-myocardial infarction patients with asymptomatic high-grade ventricular arrhyifamias, and it proved efficacious in patients resistant to other antianhythmic drugs without impairing left ventricular fimction. Cardioprotective agents and methods which employ amiodarone in synergistic combination with vasodilators and beta blockers have been described for use in patients with coronary iiisufaciency (U.S- Patent No. 5,175,187). Amiodarone has also been described for reducing arrhythmias associated with CHF as used in combination with antihypertensive agents, e.g., (S)-l-[6-ataino-2-

[[hydroxy(4-pbenylbutyl)phosplimyl3oxyl]-L-proline (U.S. Patent No. 4,962,095) and zofenopril (U.S. Patent No. 4,931,464). However, amlodarone is a difficult drug to managie because of its numerous side effects, some of wMch are serious.
The most serious long-term toxicity of amxodarone derives from its kinetics of distribanoD and elimination. It is absorbed slowly, ^ith a lew bioavailability and relatively long hiilf-Iife. These characteristics have clinically importioit consequences, including the necessity of giving loading doses, a delay in the achievemejit of full antiarrhythmic effects, and a protracted period of elimination of the drug aftesr its administration has been
discontinued.
Amiodarone also can interact negatively with numerous drugs including aprindiae, digoxin, flecainide, pbenytoin, procainamide, quinidine, and warfarin. It also has pharmacodynamic interactions with catecholamines, diltiazem, propranolol, and quinidine, resulting in alpha- and beta-antagonism, sinus arrest and hypotension, bradycardia and sinus £iirest> and torsades de pointes and ventricular tachycardias, respectively. There is also e>ddence that amiodarone depresses vitamin K-dependent clotting factorSj thereby enhant:ing the anticoagulant effect of warfarin.
Numerous adverse effects limit the clinical applicability of amiodarone. Important side eifects can occur including corneal microdeposits, hy{)erthyroidism, hypothyroidism, hepatic dysfunction, puhnonary alveolitis, photosensitivity, dermatitis, bluish discoloration, and peripheral neuropathy.
There is no Class-m agent presently marketed that can be used safely in patients with CHF. The cardiovascular dmg market is the largest in any field of drug research, and
a
an effective and safe Ciass-HI antiarrhythmic agent useful in patients with CHF is expected to be of substantial benefit. Therefore, a drug which could successfully improve the prognosis of CHF patients, but vdth a safety profile much improved over that of amiodarone, would be extremely usefiil and desired.

Brief SuTTimarv of the Invention
The subject invention pertains to novel compounds, and compositions comprising the compounds, for the trcatnaent of cardiac arrhythmias. The subject invention further concerns a method of making the novel compounds. The novel compounds are rapidly metabolized analogs of amiodarone> having the distinct and advantageous characteristic of bexQg metabolized to a less Upophihc compound. This results in an improved safety profile. The new compounds can have particular utility for treating life-threatening ventrisular tachyarrhythmias, especially in patients with c^ongestive heart failure (CHF). The product can also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation imd re-entrant tachyarrhythmias invohang accessory patliways.
More specifically, the novel compounds have ihe particular advantage of reducing the numerous side effects observed with the drugs currently available for treatment of
these cardiac arrhythmias. For example, the compound of choice cuirently used for
•
treating cardiac arrhythmias is amiodarone, which has side effects that can be serious.
Also disclosed are novel synthesis procedures for the production of the novel compounds. One of the novel syntliesis procedures essentially involves acylation of salicylaldehyde followed by cyclization and chain elongation reactions to form methyl-2-b^izcfiiraneacetate. This compound is reacted with p-anisoylchloride involving a Friedel-Craftsi type reaction which can use SnCl4 as a catalyst. Tlie compound resulting from the Friedtil-Crafts reaction is then converted from the acetate to its carboxylic acid form. The methc«ybenzoyl moiety of the compound is also convert An alternative s>'nthesis procedure, which also uses salicylaldehyde as a starting compound^ involves a cyclization step to form 2-acetylben2ofuran. This compound is then conv«5rted to its thiomorpholide derivative, which can be further converted to 2-

benzoiurane acetic acid, which is also formed in the other described synthesis procedure^ The synthesis procedures are identical after formation of 2-benzofurane acetic acid.
The subject invention thus involves the innovative development of a Class-Hi antianhythrnic agent having significantly lower toxicity than any currently available compc'imd useful in patients with congestive heart failure (CHF).
Brief P?scriptio|} ofthe Pr^wjngs
Figures lA and IB show the step-wise reaction scheme which results in the synthesis of the novel compound, methyl 2-[3-(3,5-diiodo-4-diethylaminoethoxybenz,oyl)benzofurane]acctate and its hydrochloride salt form.
Figure 2 shows an alternative synthetic scheme, "vvhere 2-benzofurane acetic acid, compciund 7, can be made fay synthesizing 2-acetylbenzofuran M from salicylaldehyde, follo^^'ed by a chain elongation procedure known as the Willgerodt-Kindler reaction in order to make the thiomorpholide derivative 14 which is then hydrolyzed to compound 7.
Figures 3A-3D show the time coxuse of ttie electrophysiological effects of equini.oiar concentrations of compound A and amiodarone in spontaneously beating guinea pig hearts. Figure 3 A is the change in atrial nite versus time plots for equin^olar concejitrations of amiodarone (v) and compound A («)»versus a control (o). Figure 3B is the change in atrioventricular (AY) interval plots for eqtiimolar concentrations of amiodarone (v) and compound A (♦), versus a control (o). Figure 3C is the change in QRS interval (intraventricular conduction time) plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o). Figure 3D is the change in QT interval (repolarization time) plots for equimolar concentrations of amiodarone (v) and compound A (•), versus a control (o).
Figures 4A-4D show the time course of the electrophysiological effects of equimolar concentrations of compound A and amiodarone in atrially-paced guinea pig hearts. Figure 4A is the change in S-H interval (atrioventricular nodal conduction time) plots for equimolar concentrations of amiodarone (#) iand compound A (v), versus a control (o). Figure 4B is the change in HV interval (His-Purkinje conduction time) plots

for eqiiimolar concentrations of amiodarone (•) and compound A (v), versus a control (o). Figure 4C is tiie change in QRS interval (intraventricular conduction time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (c). Figure 4D is the change in QT interval (repolarij^ation time) plots for equimolar concentrations of amiodarone (•) and compound A (v), versus a control (o).
Figure 5 shows time course of the electrophysiological effects of amiodarons (5 p.M) m atrially-paced guinea pig hearts.
Detailed Disclosure of the Invention
The subject invention concerns novel compounds which can produce the desired pharmacological properties of amiodarone but, unlike luniodarone, are susceptibk to biotransformation by plasma and tissue esterases to give a carboxylic acid metabolite. Carboxylic acids can forai water-soluble salts at physiological pH, and therefore can undergo renal ehmination. As a consequence, the novel compounds, cxemphfied herein by compound A, can have shorter elimination half-Ufs, Accordingly, long-term toxicity symptoms (pulmonary fibrosis, corneal microdeposits, t?tc.) decrease.
One novel compound of the subject invention, when Zi and Z2 are iodine in Formula I, has the chemical name methyl 2"[3-(3,5-diiodc>-4-diethylaminoethoxyben2oyl)benzofurane] acetate. Compounds of the invention have the cherrical structure;

wiierein Zj and Zj maybe the same, or different^ md are a halogen selected firom the group consisting of iodine, fluorine, bromine, and cWorine and X is 0, S, or NH;
m has a value from 0-10;
R=H, OH^NHj, SH» halide, allcyl, 0-alkyl, acyl, (3-acyl, axyl, 0-aiyl, substituted amine, or substituted thiol; Y - OR,, wherein Rj is a ^straight or branched chain alkyi or heterci alkyl having 1 to 8 carbon atoms, a substituted or unsubstitated axyl or heteroaryl,

wherein R>, and R3 are independently selected firom H. alkyl or heteroalkyl of 1 to 6 carbon atoms; or
m has a value from 0-10;
R„ Rj, and/or Rj may also be a moiety selected from the group consisting of C^2o ^^^> Cfl^Q heteroaHcyU C2.20 aUcenyl, aryl, C,.2o alkyl-aryl, C;j^o alkenyl-aryl, hetei'oaryl, C^,2Q allcyl-heteroaryl, C2.20 alkenyl-beteroarjd, cycloalkyl heterocycloalkyl, Ci,2o alkyl-heteroycIoaDcyl, and Cj^jo alkyl-cycloalkji, my of which may be, optionally, substituted with a moiety selected from the group consisting of C^_6 alkyl, halogen, CN, NOj^ or S02^, or wherein N is part of a cyclic or heterocyclic group, pref 5raitially, but not limited to, morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, azijidine, thiazolidine, thiazoline, tbiadiazoiidine, or tbiadiazoline. The value for n may be from 1 to 19.
R2 and R^ may be the same or different. In one embodiment, when Ri is a straight, or branched-chain alkyl or heteroalkyl, it contains at least 9 carbon atoms (n-9). In another embodiment, when R2 and R3 are alkyl or heteroalkyl moieties, they each contain at huast 7 carbon atoms (n=7).
In another embodiment, m may have a value from 0 to 10. In a preferred embodiment, m is 4- In another preferred embodiment, m is 3. In a more preferred embodiment, m is 2. In an even more preferred embodiment, m is 0. In the most preferred embodiment, m is 1.

In another embodiment, the" structure includes an iodinated benzene ring moiety. It would be understood by an ordinarily skilled artisan that oilier halides, including fiuoriae, bromine, or chlorine, can be substituted for lie iodine substituents. Thus, these other halogenated compounds axe contemplated to be included as part of the invention. In cms embodiment, when Zj and 2^ are the same, both Zj and Zj may not be iodine.
Because n can be from 1 to 19^ the term "C„.jo alkyl" refers to straight or branched chain alkyl moiety having from one to twenty carbon atom*^., including for example, methyl, ethyl, propyl, isopropyl, butyl, lert-butyl, pentyl, hexyl and the like. In onu embodiment, n is at least one, in an altemati\^e embodiment, n is at least 2.
The term '*C2.2o alkenyl" refers to a straight or branched chain alkyl moiety
"U^vK^^ 4->*.«^ 4-« ^-•.■r^^-a-i-.* AiK-tl^A-M /ff/H-t-Mn fsinA 1*t n-i r'l v^ iV **+ ^a-^P^ fSVJ-LJA VVVU LW bVVWAXfcjr VM-bWWk* t4tVt-f4-t-4'iJ hMA*«i* 4-ftM T *«.A^ n^t, «V>.«H-'V -^^^.V k^wovwaw w-r •«■- would include for example, vinyl, l-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc.
The terai "cycloalfcyl" refers to a saturated alicyclic moiety having from three to six csrbon atoms and which is optionally ben^ofiased at any available position. This temi includes for example cyclopropyl, cyclobutyl, cyclop entyl, cyclohexyl, indanyl and tctralydronaphthyl.
The tenn "heterocycloalkyl" refers to a saturated lieterocycUc moiety having from three to six atoms. One or more of these atoms maybe heteroatoms selected from N, 0, S and oxidized versions thereof, and which is optionaJly benzofused at any available positi.on. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl and tetrabydroquinolinyl.
The temi "cycloalkenyl" refers to an ahcyclic moiety having from three to six carbc»n atoms and having at least one double bond. This term includes, for example-, cyclopentenyl and cyclohexenyl.
The tenn "heterocycloalkenyl" refers to an alicyclic moiety having &om three to sbc atoms. One, or more, of these atoms may be heteroatoms selected from H O, S and oxidized versions thereof, and having in addition one double bond. This terai includes, for exanrple, dihydropyranyl

The tenii "aryl" refers to an aromatic carbocyclic radical having a single ring or two condensed rings. This tenn includes, for example phenyl or naphthyl.
The tenn "heteroaryl" refi^ to aromatic ring systesms of five to ten atoms of which at leiist one atom is selected from 0, N and S, and includes^ for example, furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
The temi "cycloimidyl" refers to a saturated ring of five to ten atoms containing the atom sequence -C(=0)NC(=0)-, The ring may ho optionally benzofused at any available position. Examples include succinimidoyl, phthalimidoyl and hydantoinyl,
The term '^benzofiised" refers to the addition of a brazene ring sharing a common bond with the defined ring system.
The temi "optionally substituted" means optionally substimted with one or more of thi5 groups specified, at any available position or positions.
The temi "halogen" means fluorine, chlorine, bromine or iodine.
The novel compounds can also be provided in their salt form. Thus, the invention includes pharaiaceutically acceptable salts, for example acid addition salts derived fiom inorg;amc or organic acids^ such as hydrohlorides, hydrabromides, p-toluenesulfonates, phosphates, sulfates, perchlorates, acetates, trifluoroi acetates, proprionates, citrates^ malC'Uates, succinates, lactates, oxalates, tartrates, and benzoates. Salts may also be deri\'ed from bases (organic and inorganic), such as alkali metal salts (e.g., magnesium or calcium salts), or organic amine salts, such as morphtoHne, piperidine, dimethylamine, or dietfcylamine salts. In addition, the ring structure moieties of the novel compounds can be dkdvatized by methods and procedures well known by those of ordinary skill in tl:ie art. For example, it would be well known that various R-groups can be attached to the six-membered ring of the benzofijran moiety of the subject cx)mpound, wherein the R groups can :include H, OH, NH^, SH, halides, alkyl, O-aHc/l, a^cyl, 0-acyl, aryl, 0-aiyl groups, substituted amines, and substituted thiols. In a preferred embodiment, R is H and X is 0.
The subject invention encompasses the novel compound A and compositions comprising these compounds. The successful appHcation of the new compounds to the treatment of CHF is evidenced by the evaluation of the liiermodynamic properties of the compound, e.g., measuring its partition coefficient between water and octanol, evaluation

of its kinetics of eliminatioii by measuring its stability in buffer and in human plasina» and evaIi:ation of its electrophysiological properties in guinea pig heart preparations. See Examples hereinbelow. More specificaUy, the novel corapounds can be used for treating life-tiareatening ventricular tachyairhythmias, especially in patients with congestive heart failu3'e. This prodxxct can provide effective management of not only ventricular tach>arrhythniias and less severe ventricular arrhythmias, but also atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways. A composition comprising a novel compound having a rapid elimination rate can offer many advantages over the cunently available antiarrhythmic agents such as aim'odarone. These advantages include:
(i) a shorter onset of action,
(ii) decreased and more manageable long-term toxicity, and
(ill) lower potential for drug int^-actions.
In addition, the novel compounds can be included in a composition comprising a second active ingredient The second active ingredient can be useful for concurrent or syneigistic treatment of arrhythmia or for the treatment of an unrelated condition which can be present with or resuU from arrhythmia or CIEF.
The subject compounds have thermodynamic properties similar to those of amiodaronCj as suggested by log P measurements, but provide the advantageous property of being rapidly metabolized in plasma to a water-soluble metabolite. More specifically, the subject compounds are Class-IU agents with electronic^ steric, and thennodynamic proptsrties comparable to those of amiodarone, but with an enzymatically labile ester group advantageously binlt into the structure such that the dmg can be readily hydrolyzed in plasma to a polar, water-soluble metabolite. TMs ^vater-soluble metabolite can be eliminated by the kidneys. This is a definite advantage over axniodarone, which is metabolized primarily in the liver. Under such conditions, the elimination of the novel compound A is increased and results in a more rapid dissociation of the dmg fi-om phosjphoUpid-binding sites. The accumulation of the compoundj which is dependent on the sveady-state tissue concentration of the drug, and theiefore on the dose, then becomes easily reversible. It follows that, upon discontinuation of a drug comprising one of the novel compoiinds, clearance from the body is more rapid. This increased elimination

makes antiarrhythmic therapy using the subject compounds or compositions compnsmg the subject compounds easi«' to manage.
Furtbermore, ttie compounds of the invention may be administered in conjunction with other compounds, or compositions thereof. These compounds, and compositions thereof, may include additional compounds known to be useful for the treatment of cardiac arrhythmias^ cardioprotective agents, antibiotics, antiviral agents, or thrombolytic agents (e,g-, streptokinase, tissue plasminogen activator, or recombinant tissue plasioinogen activator). The compounds and compositions of the invention can have particular usefiilness for treating life-threatening venlxiciJar tachyarrhythmias, especially in patients with congestive heart failure (CHF). Post-mj^ocardial infarction patients can also benefit from the administration of the subject compounds and compositions; thus, methods of treating post-myocardial infarction patients lire also provided by the subject invejition. An "individual" includes animals and huraans in need of treatement for anythmias. In a preferred embodiment, the individual is a human.
Cardioprotective agents include vasodilators and beta blockers described for use in patients with coronary insufficiericy (such as those of U.S. Patent No. S^nSjlS? or othe-rs known to the skilled artisan). Other cardioprotective agents include known anti-hypertmsive agents, e^g., (S)-l-[6-atnino-2-[[bydroxy(4-pbenylbutyl)phosphinyl}oxyl]-L-proline (ILS. Patent No. 4,962,095) and zofenopiil (US, Patent No. 4,931,464), Additional cardioprotective agents include, but are not limited to, aspirin^ heparin, warfarin, digitalis, digitoxin, nitroglycerin, isosorbide dinitrate, hydralazine, nitmprusside, captopril, enalapril, and lisinopril
The compounds and compositions also provide effective management for ventricular axrhythmias and supraventricular arrhythmias, uicluding atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways. Compounds and compositions of tlie invention are also useful for the treatment of ventricular and supra-ventricular arrbythnnas, including atrial fibrillation and fiuttei; paroxysmal supraventricular tachycardia, ventricular premature beats (VPB). sustained and non-sustained ventricular tachycardia (VT), and ventricular fibrillation (VF), OtisLcr non-limiting examples of the arrhythmias which tnay be treated by the compounds of the instant invention include:

naiTow QRS tachycardia (atrial, intra- /para-^ A-V node, or accessory patfaway),ventricular tachycjirdia, and veatricular arrhythmias in cardiomyopathy.
Following are examples which ilhistrate procedures, including the best mode, for practicing the invention. These examples should not be construed as lirmting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.
Example 1 - Svntfae&is of the Novel Compound
The novel compounds can be synthesized according to the scheme set ou: in Figures lA and IB. Below, the steps of the procedure, as shown in Figures lA-lB, are described in detail. The primary compounds involved, in the synthesis step are numbersd corresponding to the numbers provided in Figures 1A and IB.
Methyl o-fornivlphenoxvacetate: 2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erleimieyer flask with powdsred potassium carbonate (569 g), dimethylfonnamide (1,000 ml), and methyl chioroacetate (478 g) and mechanically stirred at 65 ^'C for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25 "^C. Tlie mixture was poured into cold water (0 ""C) while stirring vigorously. An oil separated that suddenly solidified. Stining was continued for 30 minutes and the solid isolated by filtratioa The product was washed with water (2 x 1,000 ml) and pressed dry. The product can also be dried iii vacuo at 25 ""C. A small sample (approx. 2 g) was purified by iiistillation. The boiling range of the pure product is 124-12S 'C at 2 mm Hg and has a melung temperature range of about 50.2'50.6^C.
Methyl 2-benzofiiranecarboxylate; 3, The crude product 2 was placed into a 5-liter 3-necked round-bottomed flask equipped with a mechanical stirrer and a water trap. Toluene (1,900 ml) was added and the solution heated at reflux temperature (111 °C) until all water had been removed. Diazabicyclounde-V-ene (T)BU) (65 g) was then added and the mixture was stirred at 111 °C, without the water trap, until the starting material was no longer present, i.e., was not detectable by TLC monitoring. Most of the solvent (90%) was then distilled off. The residue was cooled to 25 ""C, and ethyl acetate (1,000 ml) was

added. The mixtxire was transferred to a separator funnel and the organic Solution washed with2NHQ (2x l.OOOnil), then with water (1,000 ml). Diying was done over magnesium sulfate. The crude product (326.56 g) was a dark oil and was "used directly in the next step. A small sanaple was purified for the purpose of structure elucidation: the crude material (2 g) was dissolved in ethyl ether and washed with 1N KOH. Drying was done over magnesium sulfete, the material was filtered, and the solvent evaporated. The oily residue was crystallized from isopropanoU The melting range is 53,8-54"^C.
2-Hydroxvmethylfa^"zofi^^^" ^- The crude product 3 (324 g) was dissolved in anhydrous ethyl ether. The solution was kept under inert atmosphere (nitrogen or argon) and cooled to O^C in an ice bath, AIM solution of lith:ium alnminum hydride in ether (620 ml) was added dropv^e, while stiningi, over a period of 1 hour. The solution was then washed with 2 N HCl (4 x 1,000 ml), with 2 N KOH (2 x 500 ml), and with water (1,000 ml). The material was dried over magnesium sulfate, filtered, and the solvent evapc»rated. The crude product was distilled in vacuo, yielding approximately 155.36 g (1.05 mol). The boiling point is ll6'C at 1.5 mm Hg.
2-Ch)oromethvlbenzofiiran: 5. Compourid 4 (155.25 g) was dissolved in anhydrous ethyl ether (250 ml) containing dimethylformiamide (1 ml). The reaction flask was :?Iaced into an ice bath, and when the solution temperature was between CC and 4'C, thionyl chloride (124.3 g, 76.2 ml) was added diopwise, while stirring, over the pericd of 1 hour. The mixture was then stirred for anotb;er hour, washed with water (250 ml), 3% sodium bicarbonate solution (250 ml), and v;^ith water again {250 ml). The material was dried over magnesium sulfate, filtered, and the solvent evaporated. The product was distilled in vacuo, and the yield was approximately 117 g. The boiling point is about 78 °C at 1.5 mmHg.
2->CvanDmelhvIben2:ofuran: 6. Compound 5 (117 g) was added dropwise to a stining suspension of sodium cyanide (37.64 g) iu dimethyl sulfoxide (100 ml). The reac:tor was placed Scom time to time into an ice bath in order to keep the reaction temperature between20*'Cand45'C. Addition lasted 60 minutes. The reaction mixture was stirred for another 16 hours, then poured into methylene chloride (500 ml), washed

with water (500 ml, then 2 x 250 ml), and evaporated to dryness. A small sample was purified on a silica gel colimm, eluting with dichloromethane/hexanes (50:50 v/v).
2-Benzofiiraneacetic ^cid: 7. The crude cyanQmethylben2X)fi2raii, compound 6, was stirred for 6 hours in boiling water (1,000 ml) coutaming sodium hydroxide (SO g), cooled to 25 °C, then washed with methylene chloride (250 ml, then 2 x 100 ml). The pH was t*rought to 2.0 with 6 N HCl. The precipitate was extracted with methylene chloride (200 ml, tiien 100 ml, then 50 ml), dried over magnesium sulfate and the solvent evaporated. The yield was approximately 72 g.
Methvl 5'benzQfiiran.eacetate: S. Compound 7 (72 g) was dissolved in methanol (200 ml) and the solution saturated with dry HCl Tlie solution was refluxed for 2 hours and tie solvent evaporated The residue was dissolved in methylaie chloride (200 ml) and the solution washed with 5% sodium bicarbonate, and then with water (100 ml). The residue was dried over magnesium sulfate and the solveit was evaporated. The product was distilled in vacuo. The yield was approximately 67.3 g.
Methvl 2-f3-amsovIbenzofurane^acetate: 9. Co:i3pound 8 (67 g), anhydrous 1,2-dichloroetlaane (250 ml), andp-anisoyl chloride (59.55 j^) were added in a 1,000-ml flask undea- inert atmosphere. The solution was cooled in an ice bath, and SnCl4 (115 ml) was addtjd slowly. The bath was allowed to warm up to 25'C and the solution was then stiiTcd for another 24 hours. The solution was poured into an ice/water mixture (1,000 ml). The organic phase was collected, washed with 3% sodium bicarbonate (2 x 500 ml) and with water (500 ml), and then dried over magnesium sulfate. The solvent was evaj)orated. The oily residue was stirred for 24 hours into hexane (100 ml). The product is a pale yellow powder. The yield was approximate!)^ 103.3 g.
2-C3-p-hvdTQyvfaenzovIben2Qfiirane^acetic acid: 10. Aluminum powder (45 g), benzene (900 ml), and iodme crystals (345 g) were introduced in a 2-liter flask with efBcient reflux condenser and mechanical stirrer. Tne solution was placed in a water bath and stirred until most of the heat had dissipated, then stirred at reflux temperature until
the red color of iodine disappeared (approx. 30 minutes).. This mixture was cooled to
*
25'C tiien, while stirring, compound 9 (70 g) and tetrabutylammonium iodide (0.86 g)
*
wei'B added. When addition was complete, a portion of the solvent (600 ml) was distilled

away, then the remaming solution was cooled to 25 ^'C- A portion of ice-water (700 ml) was slowly added, followed by ethyl acetate (600 ml). The resulting suspension was filten^d and the residue washed with more ethyl acetate (2 x 50 ml). The organic phase was washed with more water (500 ml), then extracted with 3% sodium bicarbonate (3 x 1,200 ml). The combined aqueous phases were washed with ethyl acetate (200 ml). The aqueotjs solution was placed into an ice bath and ethyl acetate (250 ml) was added. The solution was acidified slowly using 6 N HCl while stirring. The organic phase was washed with water (200 ml), dried over magnesium sulfate, filtei:e4 and the solvent evaporated. The yield was approximately 26 g.
2^343S'Aiiod£^-A-hvdTQX^Mmmvm acid: 11, Compound 10
(25.25 g) was dissolved in water (250 ml) containing potassium carbonate (23,85 g). Iodine (47.57 g) was added and the mixture was stirred at 25 ""C for 90 minutes. Two hundred milliliters of water was added and the solution acidified with 2 N HCl The residue was filtered, then dissolved in ethyl acetate (500 ml), washed with water (500 ml), then with 5% sodium liiioaulfete (2 x 500 ml), then with water (500 ml). Theresidue was dried over magnesium sulfate, and the yield was approximately 37 g.
Methvl.2-[3-f3.5-diiodo^hv(^oxvben2ovl>benzQfiirane]acetate: 12. Compound 11 (16.4 g) was dissolved into methanol (100 ml) and concentrated sulfuric acid (1 ml). Tht; solution was refluxed for 1 hour, Hhm the solvent was evaporated. The residue was dissolved in ethyl acetate (500 ml) and washed with 5% sodium bicarbonate (300 ml). Extraction was done with 0.15 N NaOH (3 x 150 ml). The solution was acidified with 6 N HCl and extracted with ethyl acetate (2 x 150 ml), ^lat^^o^-ganic phase was washed wii 1% sodium bicarbonate (2 x 300 ml) and dried over magnesium sul^^TIic:::^'ield was approximately 11.64 g.
Methyl 2-f3'r3.5-diiodor4-diethvlaminQethQxvben2ovnben2Qfurane]acetate: A. Compound 12 (2.88 g) was dissolved in 0.1 N NaOH solution (51 ml). Methylene chloride (25 ml) is added. Benzyltrietbylammonium chloride (0.114 g) and a solution of diethylaminoetfayl chloride (0^96 g) in methylene chloride (25 ml) was then added. This was stirred for 2 hours at 25 *C. The organic phase was washed with 0,1 N NaOH (50

ml). 1N HCl (50 ml), 0.1 N NaOH (50 ml), and water (50 ml) and dried over magaesium sulfate to yield the subject compoimd.
pxaigple g - Alternative Synthetic Route for the Novel Compounds
An alternative synthetic scheme is shown in Figuj-e 2, whore 2-bmzofurane acetic acid, compoimd %> can be made by an alternative reiiction that involves synthesizing 2-acetyibenzoftiran 13 from salicylaldehyde 1 reacted wii chloroacetone, followed by a chair, elongation procedure known as fee Willgerodt-Kindler reaction in order to make the tl:domoipholide derivative 14 which is then hydrolyzed to compound 7. The remainder of the syntbdic scheme to the novel compound A is ihsn. essentially identical to Example 1.
1. Acerulbenzofuran |3. Salicylaldehyde (326/7 g) is introduced into a 3-liter 3-necked round-bottomed flask containing potassium carbonate (415 g) and acerone (500 ml). ChloToacetone (252,6 g) is then added dropwis;es v/hile stilting, over a period of 30 minutes, followed by addition of another portion of ai^etone (500 ml). The mixture is stirrsd at reflux temperature for 4 hours then cooled to 25 °C and filtered. The filtrate is eva]>orated and gives approximately 441 g of a red crystalline solid, 2-acetylbenzofuran li, which is pure enough for step 2, below. To verify the identity of the product, a small porion was distilled in vacuo (P - 0 J mm Hg) using a short path distillation apparatus, and it was detennined that the pure product distills at 80'C, yielding a white crystalline solid.
2. Benzofarane acetic acid 7. The crude 2-acetylbenzoforan H (441 g) is dissolved in morpholine (256*35 g) in a 3-liter 3-necked round-bottomed flask. Sulfur (~ 90 g) is added, and the mixture is stirred at reflux temperature (108 "* C) for 120 minutes. This reaction yields the intermediate thiomopholide derivative H. The mixture is cooled to 25 T. Methanol (750 m\\ water (500 ml), and sodium hydroxide (220 g) ai-e added, and the mixture is stirred at reflux temperature (80 ^^C) for another 4 hours. A portion of the solvent (750 ml) is then removed by distillation. The volume of the solution is brought to 6 liters wife water. NaOH (40 g) and activated decolorizing charcoal (5 g) are added and fee mixture is stirred at reflux temperature for 60 minutes, feen filtered through celite.

The mixture is then acidified to pH 2 with 12 N HCl, md the product is extracted with ethyl acetate. The extract is dried over sodiimi sulfate and evaporated, yielding appro3(imate]y 289 g of a dark solid. The crude product can be used for the next step without further purification. All physical properties of this product arc identical to compc»und Z and can be used in an identical manner afi compound 1 in the synthesis scheme described in Example 1, above.
Example 3 -Partition Coefficient of Novel Compounds
The thermodynamic properties of the new compound A can be evaluated by measuring its pardtion coefficient, P, between a pH 7.4 phosphate buffer and octanol. The buffer solution and octanol are mutually saturated before the experiment The test compounds can be dissolved in the octanohbuffer mixture at such a concentration that neithcir phase is saturated. The volume ratio between buffer and octanol is adjusted so that tlie concentration of compound in water after equilibrium is measurable. The n:iixture is shiiken for I hour and centrifuged in order to obtain complete separation of the two phas(5S. The concentration of test compound can be measured in the aqueous phase before and after equilibrium^ using a UV detection method. The partition coefBcient can be calculated using the following equation:

where P is the partition coefScientj and C^ and C^ are the concentrations of test compounds in octanol and in water, respectively. Since measurements take place only in aqueous buffer> the equation has to be modified to the following, which can be used in this expe:riment:
where Q^ is the initial amount of test compound introduced in the buffer;octanoi mixture, Q^ is the amount of test compound in buffer phase after equilibrium has been reached, and V^, iind V(^ are the volumes of buffer and octanol, respectively.

Example 4 - Stability m Buffer and Metabolism Rate in Human Plasma
Analytical method. Standard HPLC techniques can be used to determine the concentration of the drag in buffer and in human plasma using standard analytical procedures known in the art.
Stability in buffer, A known concentration of the novel compound A can be incubated in a pH 7,4 phosphate buffer at 37 "C, AUquots of the solution can be taken at various recorded intervals and diluted to the appropriate concentration for injection into the HPLC system. The hydrolysis rate constant, K^ in buffer can be calculated from the plot of drug concentration vs. time.
ls4et^bQlism rate in humai\ plasma. The same procedure as above can be used with humen plasma instead of buffer* The rate constant in plasma can be compared to the rate constant in buffer in order to give an ^proximated rale of metabolism by plasma enzymes.
Example 5 - Elftctronfavsiological Properties in Gumea Pig Heart
Antiarrhythmic activity in guinea pig heart prepaj-ations can be tested for the novel comi)ound A by methods and techniques well know3a by those of ordinary skill in the art. Anti;arrhythmic activity in guinea pig heart preparations is accepted in the art as a model for ;mtiarrhythmic activity in humans. Specifically, activity in guinea pig heart preparations is used to show that a compound depresses the spontaneous discharge, slows the s:inus node spontaneous firing rate, prolongs the effective refractory period (ERP), slows the intra-atrial conduction, suppresses atrial premature beats, prolongs the ventricular ERP, and decreases ventricular excitabili.ty. Microelectrode and pacing techniques can be used as are standard in the art. Assays to show such activity can be conducted in the isolated, superfused guinea pig S-A node-right atrial preparation. A ^11 dose-response curve for compound A can be calculated in each preparation in order to denrtonstrate the effects of different doses on S-A node spontaneous rate, atrial action potratial duration (APD) and ERP, and on ventricukir APD and ERP. The EG50 (the effective concentration that produces 50% of the maximum response), as well as the threshold and maximum doses for the compound can be determined from the full dose-response curve-

The results of electrophysiological studies carried out in guinea pig isolated hearts using the subject compound, compound A, showed that compound A displays electrophysiological properties classically associated with Class HI antiarrhythmic agents. The results of these studies are shown in Figures 3-5. Compared to the known compound, aimodarone, tiie electrophysical effects of the subject compound show several advantages. For example* on an equimolar basis, the electrophysiological effects of compound A on atrioventricular conduction, intraventricular conductirA and ventricular repolarization times are much greater than those of aKiiod-arone, both in the spontaneously beating heart (see Figures 3A, 3C, and 3D), and in tlie paced heart (see Figures 4A, 4C, and 4D). In addition, the effects of compound A on atrioventricular conduction, intraventricular conduction and ventricular repolarization times can be partially reversed upon discontinuation of the drug, whereas the effects of iuniodarone are not reversed and acmaliy tend to continue to increase even after discontinuation of the drug. Compound A is also able to more selectively increase the time of ventricular repolarization (i,e., prolctng the QT interval) relative to the changes obsen/ed on sinoatrial nodal rate and baseline atrioventricular nodal conduction time, as compared to amiodarone (Figures 3A-. 3D).
Specifically, Figures 3 A-3D show the time-dependent electrophysiological effects of a continuous 90-niinute infusion of compound A (1 jiM, n=3), amiodarone (1 ^M, n=3) and vehicle (control, n=3) on the spontaneously beatmg heart. Changes from baseline vaiues of atrial rate (Figure 3 A), A-V interval (:?igure 3B), QRS interval (Figure 3C) and QT interval (Figure 3D), respectively, are plotted as a fimction of time. Figure 3 A shows thatj compared to control hearts^ compound A and amiodarone caused significant time-dependeat reductions in atrial rate of similar magnitude. In contrast, compound A and amiodarone caused only a small prolongation of the A-V interval (Figiure 3B). The minimal effect of compound A and amiodarone on atrioventricular nodal conduction in spontaneously beating hearts can be at least partly explained by noting that atrial rate modulates the effects of drugs on atrioventricular nodal conduction. That is, concomitant slowing of atrial rate will lessen the depressant effects of drugs on atrioventricular nodal conduction. For example, in paced hearts where atrial rate is kept

constsnt, compound A (1 |iM) had a much greater effect on atrioventricular nodal conduction (Figure 4A). Unlike the effects of amiodarone^ the actions of compound A on A-V interval were reversed upon discontinuation of the drug iniusion, hereafter referred to as washout (Figure 3B). In addition, compound A but not amiodarone signifcantly prolonged tlie QRS interval, i.e., slowed intraventricular conduction (Figure 3C). During the 90-minute washout period of compound A, this effect of compound A was completely reversed. Likewise, although compound A and amiodarone significantly incre£.sed the QT interval^ the effect of compound A to prolong tlie time for ventricular repolJJrization was much greater (Figure 3D). Whereas the effect of compound A on repoliirization was partially reversed during washout, Ihe effect of amiodarone was not attenuated during washout. The average baseline valties of atrial rate, A-V interval, QRS interval and QT interval were 204.6±2.4,55.0±4.0,21,2±0.8 and 162,5±2.9, respectively. Data are shown as meaniSEM,
Figures 4A-4D show a series of separate experiments, the time-dependent electi'Ophysiological efifects of a continuous 90-minute iJifusion of compound A (1 pM, n=3): amiodarone (1 jiM, n=3) and vehicle (control, n=3) in guinea pig hearts paced at 200 beats per minute was investigated. Changes from baseline values of S-H interval (Figure 4A), HV interval (Figure 46), QRS interval (Figure 4C) and QT interval (Figure 4D), respectively, are plotted as a function of time. At equimolar concentrations, com]:)ound A d^ressed atrioventricular nodal conduction in paced hearts to a much greater extent than amiodarone (Figure 4A). The prolongation of the S-H interval caused by compound A was gradual and reached a maximum of 18 msec (i.e., a 45% increase above the baseline S-H interval) before the drug infusion was stopped. Upon washout of compound A, a large fraction (» 70%) of this effect was reversed. In contrast, amiodarone had no effect on S-H interval during the period of drug infusion* Compound A and amiodarone had no effect on His-Purkinje conduction times, i.e., the HV interval remained constant (Figure 4B). Similar to its effects on S-H inteival, compound A but not amiodarone prolonged intraventricular conduc>tion time, i.e,, increased the QRS intei-val (Figure 4C). The increase in QRS interval was gradual and reached a maximum of 1.3.5 msec (60% increase above baseline value) befo3*e the dmg infusion was

disconiinued. The effect of compound A on intraventricular conduction was completely reversed dijrmg the 90-mmute washout period. Compoimd A and amiodarone both significantly increased the QT interval. However, compoimd A was much more potent at prolonging the time for ventricular repolarization than was amiodarone CFigure 4D), Wheresas the effect of compound A on repolarization was partially reversed during washcut, the effect of amiodarone was not attenuated during washout The average baseliie values of S-H interval, AV interval, QRS interval and QT interval were 40. l=fcl .9 msec, 7,Si:0.6 msec, 223±0.7 msec, and 164.0±1,7 msec, respectively. Data are shown as meaniSEM.
Figure 5 shows a comparison of the electrophysiological actions of an equipotent (to prolong the baseline S-H interval) concentration of arcdodarone to those effects found using 1 ^M compound A. For this purpose, a concentration of 5 ]xM amiodarone was seleci:ed. Whereas amiodarone (5 ,|iM) caused a time-dependent increase in S-Hj QRS and (JT intervals, it had no effect on the HV interval Of the intervals measured, amiodarone (5 jj.M) had the greatest effect on atriovtsntricular conduction time. It prolonged the baseline S-H interval by 74 msec at 90 min of drag infusion before ihe heart went into second degree AV block. This large prolongation of S-H interval was accompanied by only a 20 msec increase in the QT intenral. On the oth^ hand, although com]30und A (1 |.iM) caused an increase of 18 msec in the baseline S-H interval at 90-min of diug treatment (Figure 3A), it was accompanied by m increase in the QT interval of 28 msec (Figure 3D). Thus, compound A, compared to amiodarone, is able to more selectively prolong the time for ventricular repolarization without causing as much depression of atrioventricular nodal conduction. Likewise, as shown in Figure 3 A, at corcparable degrees of atrial rate slowing, compound A was able to produce a much greater increase in the QT interval ia spontaneously beating hearts (Figure 3D). Taken tog
One of the major drawbacks of amiodarone in the clinical setting is its long half-life (> 30 days), which can cause severe life-threatening side effects that are slow to resolve even after discontinuation of drug therapy. The advantages of compound A over amiodarone or other currently used antiarrhythmics are that it exhibits more selective antiarrhythmic action, has a potentially shorter half-iifcj aid has cardiac effects which are more easily reversed ('washed") upon cessation of drug treatment.
Exairtple 6 - Exemplary Synthetic Pathway for Productiop of Compounds (m^2)
The following is an exemplary pathway for the synthesis of compounds of the subject invention wherein m=2 and Zj and Z^ are both iodine.
Stepl: Synthesis of 2-benzofurapvl ethvloyvcarboD\Imetbvl ketone m
122g of salicylaldehyde 1 and 350g of potassium carbonate are dissolved in 2L of acetone. While stining at room temperature, aiid slowly 165g of ethyl 4-chloroacetoacetate 2 over a period of 2 hours. Wh^sn addition is over, stir at reflux for another 4 hours. Cool to room temperature and filtei:. Wash the filtration cake with 0.5L ofaiietone. Evaporate the solvent
Step 2: Synthesis of ethvl benzofuy-ane-l-propionate (4232g of compound 3 are dissolved in SOOml of €:thanoL Cool in ice-bath and add lOOg of sodium horohydride in SOOml of water. Stir for 2 hours. Add acetic acid until the sodium borohydride has been neutralized. Cool the solution in ice-bath under an atmosphere of nitrogen and add lOg of 10% Pd/C catalyst. Stir under a hydrogen atmosphere at 15PSI until the reaction is complete, as judged by TLC. Filter through celite and evaporate organic solvents. Extract with ethyl acetate. Dry over sodium sulfate. Filter, Evaporate solvent.

step 3: Synthesis of ethvl 3-r3,5>(iiiodo-4-b vdroyvbeiizovnbeDzofurape-2^proDionate
IS)
21Sg of compound 4 aiid 409g of S^S-diiodo-^-hydroxybettzoyl diloride are
dissolved in 2L of anhydrous nietbylene chloride. Slowly add 287g of tin(IV) chloride. Stir at room temperature for 12 hours and pour into 3L of ice-water. Wash the organic phase with 5% sodium bicarbonate solution and then with 2N HCl. Diy over sodium sulfate. Evaporate. The product is crystallized from ethianol.
iStep 4: Synthesis of f3>S-diiodD^-hvdrQXvbenzov]^ben2Dfurane-2*propionic acid {€300g of compound S are dissolved in 200ml of acetic acid and 300ml of 12N HCl. Stir at 90°C for 2 hours and distill at least 400ml of solvisnt. Cool to room temperature and add IL of water. Stir well for 2 hours and filter. Wash with water. Diy.
Step 5: Svnthe&is of ggc^-butyl 3-f3>S-diiodo>4 hvdrQyvbenzQv!>benzofuraDe-2-
propijoff^ttp (7)
562g of compound 6 are stirred at 85*^C in 900g of 2-butanol and 50ml of sulfijiic
acid lor 5 hours. Cool down to room temperature. Filte:r the product. Wash twice \vith 100ml of hexane.
Step 6: Synthesis of ^^g^butvl 3^f3.S-di|odo-^t-diethv]qniipoetboyvben2ftvn
ben?:ofaraqe>;i-prppionat^ (8)
619g of compound 7 and ISOg of diethylaminoethyl chloride, hydrochloride salt, are dissolved in 2L of methylene chloride and 500ml of water. To this add 23g of beniyltriethylammonium chloride and SOg of sodium hydroxide in 2L of water. Stir vigCTously for 5 hours. Keep the organic phase. Wash with IL of water. Dry over sodium sulfate. Filter. Evaporate.

Eicaini>le of salt: hydrochloride Kalt
700g of compound * and IL of IN HCl are stirred for 2 hours. The product is filtered dry and is stirred again in 200ml of water and 2L of methyl re^'-butyi ether contauiinglOg of sodium chloride. The organic phase is dried over sodium sulfate. Filter. Evaporate the solvent

gyan^ple 7 - Uses. FormulatinTis, and AdTniniRtrations
Therapeutic and prophylactic application of the subject compounds, and compositions comprising them, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. Further, the compounds of the invention have use as starting materials or intermediates for the preparation of other useft.l compounds and compositions. The compounds of the invention arc useful for various non-th^apeutic and therapeutic purposes. It is a]:>parent fix>m the testing that the comp*ounds of the invention have effective antiarrhythmic activity. Specifically, they m:e useftil in regulating cardiac anhythmia, including atrial fibrillation, in animals and humans.
The administration of the subject compounds of the invention is useful as an antiajbythmic agent Thus, pharmaceutical compositions containing compounds of the invention as active ingredients are useful in prophylactic or therapeutic treatment of cardiac arrhythmias in humans or other mammals.
The dosage adnunistered will be dependent upon tiie response desired; the type of host involved; its age, health, weight, kind of concurrent treatment, if any; fi^equency of trtatment; therapeutic ratio and like considerations*.. Advantageously, dosage levels of the aininistered active ingredients can be^ for examples, dermal, 1 to about 500 mg/kg; orally, 0.01 to 200 mg/kg; intranasal 0.01 to about 100 lEg/kg; and aerosol 0.01 to about 50 mg/kg of animal body weight
Expressed in terms of concenrration, the actii^e ir.gredient of the invention can be presesnt in the new compositions for use demaally, intranasally, bronchially^ mtrajnuscularly, intravaginally, intravenously, or orally hi a concentration of from about 0.01 to about 50% w/w of the composition, and especially from about 04 to about 30% w/w of the composition. Preferably, tiie novel compo^ond is present in a composition from about 1 to about 10% and, most preferably, the novel composition comprises about 5% novel compound.
The compositions of the invention are advantageously used in a variety of forms, e.g., tablets, ointments, capsules, pills, powders, aerosols, granules, and oral solutions or susp'3nsions and the like containing the indicated suitable quantities of the active ingredient. Such compositions are referred to herein and in the accompanying claims

C laims
1. A compound having the structure

wherein R - H, OH, KH^^ SH, hnlide, aik)'l, O-alicj'l, acyl, 0-acyl, ijryl 0-aryl, substituted amine* or substituted ttdol;
y - OR,j wherein R^ is a straight or branched cluiin alir/I or heterc^aikyl having 1 to {\ carbon atoms, a substituted or unsubsututed ajyl or heteroaryl; or

wherein R^ and R^ are independently selected from K, alky] or heteroaliryl of 1
to 6 carbon aioms^ or w^heiein N is part of a cyclic or hciterocycUc group compnsing
morjihohnfij triazole, zdlty p>'nolidine, piperidine, piperazine, p^irole,
dihydrop>Tidinej aziridine, thia2oUdine, thia^oline, thisdia^olidine, or tliiadiazoliiie/
wherein Zj and Zj are selected from the group consisting of fluorine, broniine, and chlorine; and
X is O, S, orNH; a derivative of said compound; or a salt of said compound
2. The cotnpoimd, according to claim 1, wherein R is H and X is O,
3. The compoxmd. according to claim 1, where^in the salt of said compound is
selected from the group consisting of hydrobromide, hydrachlaride, malate, p-
toluenesulfonate, phosphate, sulfate, psrchlorate, acetate, trifluororacstats.

proprionate, citrate, malonate, succinate, lactate, tartrate, benznate, raorpholine, pipericline, dimethylamins, and diethylaminc? salts.
4. The compound, according to claim 3, whtireiii the salt of said compound k a sulfate: salt.
5. A phaimaceulical composition for treating cardiac arrhytlmiia in an animal wherein said pharmaceudcal composition comprises a compound having the stracmrs
t i
wherein K = H. OH, NH^, SH, halide,, aiicyl, 0-s.liryl, acyl 0-acyl, aryl, 0-ar/], substituted amine, or substituted thiol;
Y ^ ORp whersiin R, is a straight or branched cliain alkyl or heteroalirv'l ha\iag 1 to i carbon atoms, a substituted or unsubstituied £iryl or heteroaiyi; or

wherein Rj and R3 are independently selected fiom H, alkyl or hete^roalkyl of l to 6 carbon atoms, or wherein N is part of a cyclic ox heterocyclic group comprising moTjiholine, triazole, imidazole, pyix-olidine, piperidine, piperazine, pyrrole, dihydropyridine, azhidine, thiazolidtae, thiazoline, thisdiazolidine, or thiadia2oiin£;
wbeiein Z, and Z, are selecte;d &om the group consisting of fluorine, bromine,
aad chlorine; and
> X is 0, S, or NH; a derivative of said compound; or a saJi of said compound.

6. The phannaceurical coinpoiitiou> according tc» claim 5, wherein R is H.
7. The pharmarseutical coraposiiion, according to claim 5, wherein the sail of
said compouad is selected from the gi'oup consisting of hydrobromide, p-
TolueDesuifonatt, hydrochloride, malate, phosphate, sulfate, perchJorate, acetate,
triflucroraceiate, proprionaie, citrattj malonate, succinxits, lactate, tartraie, benzoate,
morprioline, piperidine, dimethylaniins. and diethyla-mine salts.
8. The pharmac;iuti'cal coniposition, accorduig to claim 7, wherein the salt of
said compoimd is a sulfate salt.
9. The pharmaceutical composition, according to claim 5, whersm said
pharnacemical composition comprises about 0.01% lo about 50% of said compound.
* 10. The pharmaceutical composition, accor^^ing to claim 5, wherein said comf osition comprises from about 0.1% to about 30% of said compound.
11. The pharmaceutical composiiioa, according; to ciaiui 5, wherein said
phannaceudcal compodtion comprisies from about 1% to about 10% of said
conii)ound.
12. A method for treating cardiac an*hythmia in an aniniai, wherein said
method comprises administering an effeciive amount of a compound having tlis

wher£:m R =^ H, OH, NK2, SH, balide, atkyl, 0-aIl:y!, acyl, 0-acyl, aiyl, 0-ar>'l substituted amine, or substimted thiol;
Y = ORj, where:j} Rj is a straight or branched cliain al5Ql or hetsroalk^^ having I to S carbon atoms, a substituted or uusubstituted aryl or heteroaryl; or

wherein It^ and R3 are independently selected firom H, alk>^I or heteroaUcyl of 1 to 6 c;arbon atoms, or wherein N is part of a cyclic or httterocyclic group comprising morpholine, triazole, imidazole, pyiroHdine, piperidine, piperazine, pyixole, dihViiropyridine, aziridine, thiazolidine, thia:2oIine, thiadiazolidine, or ihiadiazoline;
wherein Z^ and 2^ are selected from the group consisting of fluorine, bromiiie, and iihlorine; and
X is O, S, or Nli; a derivative of said conipound; or a salt of said compound.
13. The method, according lo claim 12, wherein R is H and X is O.
14, The method, according to claim 12j wherein said composition is
adn^inistered to a mananal.
13. The method, according 10 claim 14> wherein said composition is adn'iinisteTed to a human.
16. The method, according to claim 12, v/herein said composition is administered in combination with a second pharmaceutical composition.

wherein R = H, OH, NH,, SH, halide, aUcyl 0-alkyl, acyl, 0-acyI, aryl, 0-aryl, substituted amine, or substituted thiol;
y = ORj, wherein Rj is a straight or branched chain alkyl or heteroalkyl having 1 to S carbon atoms, a substituted or unsubstituted aryl or heteroaryl; or

wherein R^ and R3 axe independently selected firom H, alkyl or heteroalkyl of 1 to 6 carbon atoms, or wherein N is part of a cychc or hstsrocyclic group comprising morDholine, triazolCj imidazole, pyrrolidine, piperidin:;, piperazine, pyrrole, dihydropyridxnej aziridine, thiazolidine, thiazoline, thiadiazolidine, or thiadiazohne;
wherein Zj and 7^ are iodine;
XisO, S,orNH;and
wherein said salt is selected from the group cor.sisting of hydrobromide, p-toiuenesulfonate, phosphate, sulfate, perchlorate, ai^etate, trifluororacetate, propirionate, citrate, malonate, succinate, lactate^ ta:rtrate, bensoate, morpholinej piperidine, dimethylamine, and diethylamine salts.
IS. The compound, according to claim 17, whtirein R is H and X is O.

19. The compound, according to claim 17, wherein the salt of said compound is a sulfate salt,
20. A compound having the structure

wherein Zj and Z^ may be the same, or diffexent, and are selected from the grou]3 consisting of iodine, fluorine, bromine, and chlorine and X is 0, S, or NH;
m has a value fi-om 0-10;
R = H, OH, KTH^, SH, haiide, alkyl, O^alkyl, acyl. 0-acyl, aryl, 0-aryl, subsiituted amine, or substituted thiol; Y - OR,, whensin R, is a straight or branched chain alkyl or hetero alkyl having 1 to 8 carbon atoms, a substituted or unsubstituted aryl or heteroaryl, or
R.
"R3
wherein R2, and R^ are independently selected from H, alkyl or heteroalkyl of 1 to 6 atoms; or wherein
m has a value fi-om 0-10;
Rj is a moiety selected from the group consistiag of C„.JQ alkyl, Cj,,^o hetexoalkyl, C2_2o aUcenyl, aryl, C^^oo alkyl-aryl, C^.^^. alkenyl-aryl, heteroaryl, Cj^jo alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C^.^^ alkyl-hetei'oycloalkyl, and Ci.2p alkyl-cycloalkyl, any of v/liicb maybe substituted with a moiety selected from the group consisting of C^^^ alkyl, halogen, CN, NO^, and SO^;

Rj and R3 may be the same or different and are selected from the group consisting of C^2o alkyl, C^^^o heteroalkyl, C^.jo allcenyl, a:ryl, C1.20 alkyl-aryl, C^so alkenyl-aryl, heteroaryl, C1.20 alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloaUcyl, heterocjycloalkyl C^.io alkyl-heteroycloalkyl, and C^^2o ali:yl-cycloalkyl, any of which may be;, optionally, substituted with a moiety selected frcm the group consisting of Cj,^^ alkyl, lialogen, CN, NO^, and SOa^;
n is one; or
wherein N is part of a cyclic or heterocyclic group selected from the group consisdng of morpholine, triazole, imidazole, pyrrolidine, piperidinej piperazine, pyrrolij, dihydropyridine, aziridine, thiazolidine, thia:ioliae, tbiadiazoHdine, or thiadifizoline.
21. The compound, according to claim 20, AA'herein the salt of said compound
is selected from the group consisting of hydrobromide, hydrochloride, malate, p-
toluer.esulfonate, phosphate, sulfate^ perchlorate, acetat€i> trifluororacetate,
proprionate, citrate, malonate, succinates lactate, tartrate, benzoate, morpholine,
piperidine, dimethylamine, or diethylaniine salts,
22. The compoimd, according to claim 21, v^herein the salt of said compoxmd
is a sulfate salt.
23. A pharmacejutical composition for treating cardiac arrhythmia in an animal
wherein said pharmaceutical composition comprises a compound having the structure

wherein Z^ and Zj may be the same, or different, and are selected from the group consisting of iodine, fluorine, bromine, and chlorine and X is O, S. or NH;
m has a value from 0-10;
wherein R = H, OH, NH^, SH, halide, alkyl, 0-all7l, acyl, 0-acyl, aryl» 0-aryl, substi'tuted amine, or substituted thiol; Y - ORi, wherein R^ is a straight or branched chain alkyl or hetero alkyl having 1 to 8 carbon atoms, a. substituted or unsubstituted aryl o:' heteroaryl, or

whei'cin Rj? ^^ ^^3 are independently selected from H, alkyl or heteroalkyl of 1 to 6 atoms; or wherein
m has a value from 0-10;
R^ is a moiety selected from the group consisting of C^^^jo alkyl, C^.^o heteroalkyl, Cj.20 alkenyl, aryl, Cj.20 aJkyl-aryl, Cj.jo alkenyl-aryl, beteroaryl. Ci,2o ^^^ heteroaryl, C2.20 alkenyl-heteroarylj cycloalkyl, heterocycloalkyl, C1.20 allcyl-heteroycloalkyl, and C^^jo alkyl-cycloalkyl, any of wliich maybe, optionally, substituted with a group selected from the group consisting of C^,^ alkyl, halogen, CN, NO., and
Ro and R3 maybe the same or different and £ire selected from the group consisting of C^,2o alkyl, C„.2o heteroalkyl. C2.20 alkenyl, aryl, C,.2o alkyl-aryl, Cs.io alkenyl-aiyl, heteroaryl, C^^^o alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C^^^o alkyl-heteroycloaikyl, and Cj,2o alkyl-cycloalkyl, any of which may l^e^ optionally, substituted with a moiety selected firom the group consisting of Cj.^ alkyl halogen, CN, NO2, and SOj^;
n is one;
or wherein N is part of a cyclic or heterocyclic gjoup selected from the group consisting of morphoHne, triazole, imidazole, pyrrolidine, piperidine', piperazine, pyrrctle, dihydropyridine. aziiidine, tbiazolidine, tbiazoline, thiadiazolidinej or thiadiazoline.

24. The pharmaceutical composition, accordtag to claim 23, whereiu R is H.
25. The pharmaceutical composition, according to claim 23, wherein the salt
of said, compound is selected from the group consisti^ig of hydrobromide, malate,
hydrocihloride, p-toluenesulfonate, phosphate, sul&te* perchlorate, acetate,
trifluororacetatej proprionate, citrate, malonate, succinatti, lactate, tartrate, and
benzoiite, morpholine, piperidine, dimetbylaminej ordielhylaniiiie salts,
26. The pharmaceutical composition, accordmg to claim 25, wherein the sal:
of said compound is a sulfate salt,
27. The pharmaceutical composition, according to claim 23, wherein said
pharmaceutical composition comprises about 0.01% to about 50% of said compound.
28. The phamiaceutical composition, according to claim 23, wherein said
composition comprises from about 0.1% to about 3C'% of said compound.
29. The pharmaceutical composition, according to claim 23, wherein said
pbarraaceutical composition comprises from about 1% to abom 10% of said
w
comp'ound.
30. A method for treating cardiac arrhythmia in an animal, wherein said

wherem Zj a^d Zj may be the same, or different, :and are a halogen selected from the group consisting of iodine, fluorine, bromine, a:id chlorine and X is 0, S, or
NH;
m has a value from 0-10;
wherein R = H, OH, NH., SH, haiide, alkyl, 0-aIlcyi, acyl, 0-acyl, aryl, O-aryl, substituted amine, or substituted thiol; Y = OR3, whereii R, is a straight or branched chain allcyl or hetero aD^'l having 1 to 8 carbon atoms, a substituted or unsubstituted aryl 01 heteroaryl, or

wherein Rj, and R3 are indepeixdently selected from H, alkyl or heteroalkyl of 1 to 6 atoms; or wherein
m has a value from 0-10;
R^ is a moiet}' selected from the group consisting of Cr,.2o ^^l Cn-20 heteroalkyl, C2.20 alkenyl, aryl, C].2o alkyl-aryl, C.^o alkenyl-aiyl, heteroaiyl, Cj^o alkyl-heleroaryl, C^jo alkenyl-heteroaryl, cj^cloalkyl, heterocycloalkyl, C^^o aBcyl-heteroycloallcyl, and Cj^jo alkyl-cycloallcyl, any of wliich maybe, optionally, substituted with a group selected from the group consisthig of Cj^ ^Jkyl, halogen, CN, NO^, and
R2 and R3 may be the same or different and are selected from the group consisting of Cn^o alkyl, C^.^^ heteroalkyl, 62.^0 alkeryl, aryl, C).2o alk^l-aiyl, €2,20 alkenyl-aryl, heteroaryl, Cj^^ alkyl-heteroaryl, C2.20 alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C, ^p alkyl-heteroycloalkyl, and C^.20 alkyl-cycloalkyl, any of which may l)e, optionally, substituted with a moiety selected fi-om the group consisting of Cj.^ alkyl, halogen, CN, NO., and SO^^;
n is one; or
wherein N is paxt of a cyclic or heterocyclic group selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine.

pyrrole^ dihydropyridxne, aziridine, tbiazolidine, lhia2oIinep thiadiazolidine, and thiadiazoline.
31. The method, according to claim 30, wherein R is H and X is O.
32. The method, according to claim 30, wherein said composition is administered to a mammal.
33. The method, according to claim 30> wherein said composition is administered to a human.
34. The method^ according to claim 30, wherein said composition is administered in combination with a second pharmaceutical composition.

A compound substantially as herein described with reference to the accompanying drawings.
A pharmaceutical composition substantially as herein described with reference to the accompanying drawings.

Documents:

480-chenp-2003-abstract.pdf

480-chenp-2003-assignement.pdf

480-chenp-2003-claims duplicate.pdf

480-chenp-2003-claims original.pdf

480-chenp-2003-correspondnece-others.pdf

480-chenp-2003-correspondnece-po.pdf

480-chenp-2003-description(complete) duplicate.pdf

480-chenp-2003-description(complete) original.pdf

480-chenp-2003-drawings.pdf

480-chenp-2003-form 1.pdf

480-chenp-2003-form 26.pdf

480-chenp-2003-form 3.pdf

480-chenp-2003-form 5.pdf

480-chenp-2003-other documents.pdf

480-chenp-2003-pct.pdf

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Patent Number

209636

Indian Patent Application Number

480/CHENP/2003

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

05-Sep-2007

Date of Filing

04-Apr-2003

Name of Patentee

M/S. ARYX THERAPEUTICS

Applicant Address

2255 Martin Avenue, Suite F, Santa Clara California 95050

Inventors:

#	Inventor's Name	Inventor's Address
1	DRUZGALA, Pascal	1512 Mission Boulevard Santa Rosa, CA 95409
2	MILNER, Peter, G	14690 Manuella Road Los Altos Hills, CA 94022

PCT International Classification Number

A61K 31/343

PCT International Application Number

PCT/US2001/031305

PCT International Filing date

2001-10-04

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	09/680,880	2000-10-06	U.S.A.