EP1109801A1 - Substituted dihydrobenzopyrans useful as antiarrhythmic agents - Google Patents

Abstract

Disclosed are novel dihydrobenzopyran compounds useful as antiarrhythmic and antifibrillatory agents. The compounds have a structure according to formula (A), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined in the specification. Formula (A) also includes optical isomers, diastereomers or enantiomers. Also disclosed are pharmaceutical compositions and methods of treating disorders and conditions characterized by antiarrhythmic activity using these compounds or the pharmaceutical compositions containing them.

Description

SUBSTITUTED DIHYDROBENZOPYRANS USEFUL AS ANTIARRHYTHMIC AGENTS

TECHNICAL FIELD

This invention relates to compounds and pharmaceutical compositions comprising these compounds, useful in treating cardiac arrhythmia and/or cardiac fibrillation.

BACKGROUND OF THE INVENTION

The compounds of this invention are active as antifibπllatory and antiarrhythmic agents These compounds exhibit broad efficacy against cardiac arrhythmia and fibrillation and can be satisfactorily applied to substantially alleviate and/or prevent arrhythmia and fibrillation. In addition, they exhibit a lower incidence of some of the undesirable side effects than do many conventional antiarrhythmic therapies. An additional benefit of the compounds described herein is that they exhibit both anttfibπllatory and antiarrhythmic activity; most conventional therapies generally do not exhibit efficacy as antifibπllatory agents. See, e.g. Coplen, S. E et al., "Efficacy and Safety of Quimdme Therapy for Maintenance of Sinus Rhythm after Cardioversion: A meta-analysis," Circulation. Vol. 82, pp. 1106-1116 (1990), and Echt, D. S. et al., "Mortality and Morbidity in Patients receiving Encamide, Flecainide, or Placebo. The Cardiac Arrhythmia Suppression Trial", N. Engl. J Med.. Vol. 324, pp. 781-788 (1991), both hereby incorporated by reference herein.

In a healthy, structurally sound heart, the precise, sequential electrical activation, then deactivation, of the entire cardiac muscle that occurs unerringly with each beat is characterized as normal cardiac rhythm. Arrhythmias are characterized as occurrences of abnormal electrical activity that can interfere with normal cardiac rhythm. The abnormal electrical activity can interfere with the initiation of, and/or the uniform spread of, the electrical wave (i.e depolarization followed by repolaπzation of the cardiac muscle) that triggers the heart to contract. The disruption of the smooth, cyclical process of cardiac function associated with normal cardiac rhythm by the existence of arrhythmias is, in some instances, life-threatenmg.

Arrhythmias range in severity from relatively benign (consisting of asymptomatic and infrequent premature ventricular complexes [PVCs]) to life-threatenmg (consisting of ventricular fibrillation, and sustained ventricular tachyarrhythmia). For an excellent review of arrhythmias and an overview of antiarrhythmic therapy, see, e.g. Bigger, Thomas J., "Antiarrhythmic Treatment: An Overview", Am. J. Cardiol , Vol. 53, pp. 8B-16B, 1984; Reiffel, J. A. "Prolonging survival by reducing arrhythmic death: pharmacologic therapy of ventricular tachycardia and fibrillation," Am. J. Cardiol , Vol. 80(8A), pp. 45-55 (1997); Ganz, L. I.; Antman, E. M. "Antiarrhythmic drug therapy m the management of atrial fibrillation," J_ Cardiovasc. Electrophys., Vol. 8(10), pp. 1175-89 (1997), all hereby incorporated by reference herein. Life threatening arrhythmias are noted as a leading cause of death worldwide. For instance, it is estimated that sudden cardiac death resulting from ventricular fibrillation kills approximately 400,000-600,000 people in the United States each year. U.S. Department of Health and Human Sciences (1985) NCHS Monthly Vital Statistics Report 33:8-9.

Arrhythmias are generally classified into two types' 1) supra ventricular arrhythmias (for example, atrial fibrillation and flutter) and 2) ventricular arrhythmias (for example, ventricular tachyarrhythmia and ventricular fibrillation and flutter).

Supraventricular arrhythmias are generally not life threatening. Individuals with these arrhythmias may experience a wide range of symptoms, from slight to severe intensity. These individuals may feel the physical sensation of missed beats, extra beats, and/or flutter, may occasionally feel slightly light-headed or dizzy, and may have shortness of breath and/or chest pa . Since this situation is, m fact, generally not life threatening, more aggressive therapies such as conventional antiarrhythmic drugs sometimes are not prescribed, because the side effects usually associated therewith may not be acceptable for a non-hfe-threatening condition. However, the compounds of this invention are generally better tolerated than many of the conventional, currently available antiarrhythmic s; therefore, they would likely be an acceptable therapy for individuals suffering from supraventricular arrhythmias and would substantially alleviate the discomfort these individuals experience.

Ventricular arrhythmias, on the other hand, are potentially much more serious and have been classified into three groups: 1) benign; 2) prognostically-sigmficant (potentially lethal); and 3) life threatening (lethal). See, e.g. Morganroth, J. and Bigger, J. T., "Pharmacological management of ventricular arrhythmias after the Cardiac Arrhythmia Suppression Trial", Amer. J. Cardiol. Vol. 65, pp. 1497-1503 (1990), hereby incorporated by reference herein (Morganroth).

Individuals with benign arrhythmias exhibit very low risk of death, cardiac scarring, and heart disease. Benign ventricular arrhythmias are relatively common and account for approximately 30% of all ventricular arrhythmias. Benign arrhythmias, such as premature ventricular complexes (PVCs), pose minimal risks to individuals and rarely require antiarrhythmic therapy. However, the PVCs may be of a frequency or complexity to provide alarming symptoms Individuals who exhibit "prognostically-significant" arrhythmias may benefit from antiarrhythmic therapy. These individuals generally have suffered a myocardial infarction and may have PVCs and/or episodes of non-sustamed ventricular tachyarrhythmia, either symptomatic or asymptomatic. They may have not immediate, urgent life-threatenmg symptoms, and are not typically m danger of death They are, however, at a significantly greater risk of sudden death than the general populace, and, accordingly, would be at a lessened risk of cardiac failure with therapy from the compounds of this invention. See Morganroth & Bigger at 1498.

Others exhibit sustained ventricular tachyarrhythmia or ventricular fibrillation which are life -threatening These ventricular arrhythmias generally produce symptoms such as syncope, heart failure, myocardial ischemia or hypotension These patients have the highest risk of sudden cardiac death and usually the most severe form of underlying cardiac disease. (Morganroth p. 1498).

The pharmacotherapy of cardiac arrhythmias has over the years employed drugs with diverse mechanisms of action. These drugs have been classified by their actions on the characteristic shape of the cardiac action potential. See Vaughan-Wilhams, E. M., "A classification of antiarrhythmic actions reassessed after a decade of new drugs." J. Gin. Pharmacol. Vol. 24, pp. 129-147 (1984). More recently, a classification has been proposed on the basis of their individual, characteristic effects on ion channels and receptor systems of the myocardium. See "The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology," Circulation. Vol. 84 (4), pp. 1831-1851 (1991).

In the Vaughan-Wilhams scheme, Class I antiarrhythmic drugs act to slow the upstroke of the cardiac action potential, and slow the conduction velocity of the electrical impulse across the heart. These agents act principally by blocking myocardial Na channels.

Class II antiarrhythmic drugs prolong the interval between cardiac action potentials, i.e., they slow the rate at which the heart beats. These compounds act by blocking catecholamme receptors of the heart.

Class III antiarrhythmic agents prolong the duration of the cardiac action potential. This leads to an increase in the refractory period of the heart without a reduction in the conduction velocity of the electrical impulse. These compounds act by, for example, blocking myocardial potassium currents. The pharmacotherapy of cardiac arrhythmias has been undergoing major changes since 1991, when the Cardiac Arrhythmia Suppression Trials (CAST) showed that the Class I antiarrhythmic agents encaimde, flecamide, and moπcizme were associated with an increased risk of sudden cardiac death. As a result of the CAST trials, the use of Class I agents is generally avoided in patients who have structural heart disease, i.e. a prior myocardial infarction. See Morganroth.

Instead, the focus of antiarrhythmic pharmacotherapy has shifted to the use of Class HI agents. For instance, m the CASCADE clinical trial, the antiarrhythmic agents d,l- sotalol and amiodarone were shown to have neutral or slightly beneficial effects on mortality. Amiodarone and sotalol share certain mechanistic features that may have contributed to these results, including a mixed Class LI and Class HI antiarrhythmic action See "Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study)," Am. J. Cardiol.. Vol. 72 (3), pp. 280-7 (1993).

Two major clinical trials (the SWORD trial and the DIAMOND trial) have been conducted to test whether a pure Class III agent can reduce the incidence of sudden cardiac death in patients with depressed left ventricular function following an acute myocardial infarction. The SWORD trial was designed to test whether a pure Class III antiarrhythmic agent, d-sotalol, in patients with depressed ventricular function following acute myocardial infarction or with symptomatic congestive heart failure, would reduce the incidence of sudden cardiac death. The trial was terminated prematurely because of excess mortality in the d-sotalol-treated group. See Waldo, A. L.; Camm, A. J.; deRuyter, H.; Friedman, P. L.; MacNeil, D. "Effect of d- sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d- Sotalol," Lancet. Vol. 348(9019), pp. 7-12 (1996).

In the DIAMOND trial, a neutral effect on mortality was observed with the highly potent and selective Class III agent dofetilide. See "Dofetilide m patients with left ventricular dysfunction and either heart failure or acute myocardial infarction: rationale, design, and patient characteristics of the DIAMOND studies. Danish Investigations of Arrhythmia and Mortality ON Dofetilide," Clinical Cardiology. Vol. 20 (8), pp. 704-10 (1997).

Another pure Class III antiarrhythmic agent, lbutihde, has recently gained marketing authorization for the rapid termination of atrial arrhythmias to sinus rhythm. The drug is associated with significant incidence of potentially dangerous ventricular arrhythmias, a fact that severely restricts its utility. See Foster, R. H.; Wilde, M. I.; Markham, A. "lbutihde : a review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation," Drugs, Vol. 54(2), pp. 312-330 (1997).

The compounds of the present invention are Class III antiarrhythmic agents with mechanistic features that herald a significant advance over existing antiarrhythmic agents in the treatment of cardiac arrhythmias.

The mechanism by which Class HI antiarrhythmics typically achieve their effects on the cardiac action potential is by inhibiting the efflux of K ions from cardiac myocytes The mam outward K conductance that terminates the plateau phase of the human cardiac action potential is termed the delayed rectifier current, Ljc- Cellular electrophysiological, molecular biological, and genetic studies have demonstrated that the Iκ current is carried by two kmetically and molecularly distinct ion channel complexes. They are named after their distinct current sub-types, I _J (rapidly activating and deactivating; carried by the HERG protein), and IK_S (slowly activating and deactivating; carried by the KvLQTl/minK protein complex). See Sangumetti, M. C; Jiang, C; Curran, M. E.; Keating, M. T. "A mechanistic link between an inherited and an acquired cardiac arrhythmia and HERG encodes the LKr potassium channel," Cell. Vol. 81(2), pp. 299-307 (1995) and Sangumetti, M. C; Curran, M. E.; Zou, A., et al. "Coassembly of KvLQTl minK (IsK) proteins to form cardiac LKs potassium channel," Nature, Vol. 384, pp. 80-83 (1996). Compounds which selectively block IK_J- (such as dofetilide and d-sotalol) have been associated with an enhanced risk of proarrhythmia, especially at slow heart rates. See Nair, L. A., Grant, A. O. "Emerging class III antiarrhythmic agents: mechanism of action and proarrhythmic potential," Cardiovasc. Drugs Ther., Vol. 11(2), pp. 149-167 (1997) and Colatsky, T. J.; Argentieπ, T. M. "Potassium channel blockers as antiarrhythmic drugs," Drug Dev. Res.. Vol. 33(3), pp. 235-49 (1994) and Hondeghem, L. M ; Snyders, D. J "Class HI antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence," Circulation. Vol. 81(2), pp. 686-90 (1990).

The compounds of the present invention act primarily by the blockade of IK_S- Accordingly, they can terminate atrial and ventricular arrhythmias, as well as reduce their frequency and severity. IK_S blockers can also reduce the risk of sudden cardiac death. See U.S. Pat. 5658901 to Clare on D. A., Liverton N., Selmck H. G., issued 1997 and Selnick, H. G.; Liverton, N. J.; Baldwin, J. J., et al. "Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current DCs by (R)-2-(2,4-(l,l,l-trιfluoromethyl))-N-[2-oxo-5-phenyl-l-(2,2,2- trιfluoroethyl)-2,3- dιhydro-lH-benzo[e][l,4]dιazepιn-3-yl]acetarmde," J. Med. Chem.. Vol. 40 (24), pp. 3865- 3868 (1997). Since the KvLQTl ion channel and/or the I _S current may have additional physiological roles m certain other tissues, such as the stimulated production of gastric acid, the compounds of the current invention can be used to reduce gastric acid secretion. This makes them useful in the treatment of gastric (duodenal) ulcers. See Wargh, R.; Riedemann, N.; Bleich, M.; Van Dπessche, W.; Busch, A. E.; Greger, R. "The cAMP -regulated and 293B-mhιbιted K+ conductance of rat colonic crypt base cells," Pfluegers Arch., Vol. 432 (1), pp. 81-88 (1996) and Suessbπch, H.; Bleich, M.; Ecke, D., et al. "Specific blockade of slowly activating I(sK) channels by chromanols - impact on the role of I(sK) channels in epitheha," FEBS Letters. Vol. 396 (2-3), pp. 271-5 (1996). The compounds of the current invention can also be used for the treatment of diarrhea, see van Kuijck, M. A.; van Aubel, R. A. M. H.; Busch, A. E., et al "Molecular cloning and expression of a cyclic AMP- activated chloride conductance regulator: a novel ATP -binding cassette transporter," Proc. Natl Acad. Sci. U.S.A . Vol. 93 (11), pp. 5401-5406 (1996)

The compounds of the present invention contain a heterocychc ring system referred to as a dihydrobenzopyran. Cromakahm (compound 1 below) is a 4-amιdo-2,2-dιalkyl-3- hydroxybenzopyran antihypertensive that has shown promise in the treatment of asthma or of high blood pressure.

Cromakahm and related 4-amιdo-2,2-dιalkyl-3-hydroxybenzopyrans have been investigated extensively and summaries of this field are readily available. See Evans, J. M.; Hamilton, T. C, Longman, S. D.; Stemp, G. Potassium Channels and their Modulators' From Synthesis to Clinical Experience. Bristol, PA. Tayler & Francis, 1996. These compounds exert their pharmacological actions by stimulating the ATP-sensitive K current (IK-ATP) ^ιn smooth muscle cells, such as are found m the vasculature of the airways or in peripheral blood vessels Activating J.K-ATP results in a hyperpolaπzing response and eventually the relaxation of these muscle cells and dilation of the vessel. This stimulation of an outward K conductance is the opposite effect that is characteristic of

+ Class HI antiarrhythmic drugs, which block outward K currents.

Benzopyrans of structure similar to that of cromakahm have been described m the literature: U.S. Patent 5,082,858 discloses certain 2,3-dιhydro-2,2-dιmethyl-3-hydroxy- benzopyrans. These are said to be antithrombotics and to have effects on the central nervous system (CNS), primarily as antidepressants. The compounds are also said to have been studied for cardiac effects and they had insignificant or no activity (see Col. 1 and 8)

European Patent Application 389,861 discloses certain 3-hydroxy-2,2- dimethyldihydrobenzopyrans that are taught to be potassium channel openers and activators of IK-ATP They are said to have effects like cromakahm, such as vasodilatmg and antihypertensive effects.

U.S. Patent 4,882,353 discloses certain 2,2-dιmethyldιhydrobenzopyrans that are taught to be potassium channel openers and activators of IK-ATP They are said to have effects like cromakahm, such as vasodilatmg and antihypertensive effects as well as antithrombotic effects.

U.S. Patent 5,206,252 discloses 4-thιazadolyl-benzopyrans. They are said to have effects like cromakahm, such as vasodilatmg and antihypertensive effects, as well as amelioration of urinary incontinence.

Soil, R. M.; Dolhngs, P. J.; McCaully, R. "N-sulfonamides of benzopyran-related potassium channel openers: conversion of glybuπde insensitive smooth muscle relaxants to potent smooth muscle contractors," Bioorg. Med. Chem. Lett., Vol. 4(5), pp. 769-73 (1994) describes 6-tπfluoromethoxy-4-(( 1,1,1 -trιfluoromethyl)sulfonylammo)-substιtuted dihydro- benzopyrans that were evaluated m different tissues and may be K channel blockers, although the text is not clear.

European Patent 807,629 discloses two different types of 2,3-dιhydro-4- sulfonamidobenzopyrans said to be K channel blockers. The reference teaches on page 11, line 30, that removal of the 3-hydroxy substituent enhances the potency of action. It is also taught that the preferred absolute stereochemistry of the 3 and 4 positions is 3S,4R. See Lohrmann, E.; Burhoff, I.; Nitscke, R. B.; et al. "A new class of inhibitors of cAMP- mediated Cl secretion m rabbit colon, acting by the reduction of cAMP-activated K conductance," Pflϋgers Arch. - Eur. J. Phvsiol., Vol 429, 517-530 (1995); and Suessbπch, H.; Bleich, M.; Ecke, D.; et al. "Specific blockade of slowly activating IsK channels by chromanols - impact on the role of IsK channels in epitheha," FEBS Lett. Vol. 396, 271- 275 (1996). The compounds of the present invention differ from those described in these references, by virtue of the surprising and unexpected increase in pharmacological potency of 3-hydroxy-4-sulfonamιdobenzopyrans when certain substituents are placed in the 6- position of the benzopyran. Furthermore, the preferred compounds of the present invention have the 3R,4S stereochemistry. This is in direct contrast to the teachings of Lohrmann et al. and Suessbπch et al., which suggest the preferred stereochemistry is 3S,4R. Applicants have also discovered that the 3R,4S preference also applies to those compounds described by Lohrmann et al. and Suessbπch et al.

The compounds of the present invention differ significantly in their chemical structure, pharmacological actions and therapeutic utility from certain 2- spiropipeπdmylbenzopyran derivatives, such as MK-499. See Spector, P. S.; Curran, M. E.; Keating, M. T.; Sangumetti, M. C. "Class III antiarrhythmic drugs block HERG , a human cardiac delayed rectifier K+ channel: open-channel block by methanesulfonamlides," Ore. Res., Vol. 78(3), pp. 499-503 (1996) and Lynch, J. J., Jr., Wallace, A. A ; Stupienski, R. F., HI, et al. "Cardiac electrophysiologic and antiarrhythmic actions of two long-acting spirobenzopyran pipeπdme class IH agents, L-702,958 and L- 706,000 [MK-499]," J. Pharmacol. Exp. Ther.. Vol. 269(2), pp. 541-554 (1994) These compounds are known to block Iκr_> and have been associated with an increased predisposition to cardiac arrhythmias in animal studies and humans.

SUMMARY OF THE INVENTION The compounds of this invention are 2,3-dιhydro-2,2-dιmethyl-3-hydroxy-4- sulfonamidobenzopyran derivatives of Formula (A):

R,

wherein

(a) R] is selected from haloalkyl, haloacyl, NR7SO2R.8, and NR7COR8;

(b) each R2 is independently selected from hydrogen, alkyl, halo, alkoxy, and alkoxyalkyl;

(c) R3 is lower alkyl, or together with R4 forms a spirocycle of from 4 to 7 members;

(d) R4 is lower alkyl, or together with R3 forms a spirocycle of from 4 to 7 members;

(e) R5 is selected from hydrogen, alkyl, aryl, arylalkyl, and haloalkyl; (f) R6 is selected from alkyl, aryl, cycloalkyl, arylalkyl, haloalkyl, and alkylamino;

(g) R7 is selected from hydrogen and alkyl; and (h) Rs is C1-C4 haloalkyl.

This structure also includes any single diastereomer or enantiomer of Formula (A), or mixtures of diastereomers or enantiomers of Formula (A). Also included in the scope of the present invention is a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof, or any other derivative which is bioconverted to Formula (A). The invention further relates to pharmaceutical compositions containing the compounds of Formula (A) and methods of delivering these compounds and pharmaceutical compositions, for treating arrhythmic disorders and conditions, gastric ulcers, and diarrhea.

The compounds of this invention are antiarrhythmic agents that exhibit less of the undesirable side effects (e.g., pulmonary toxicity, cardiac depression, and neurological effects nonspecific to cardiac tissue) associated with many conventional antiarrhythmic therapies. In addition the compounds of this invention are useful in the treatment of diarrhea and of ulcers.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention bear a unique substitution pattern and opposite stereoselectivity than cromakalim-hke benzopyrans, which results m an unexpected increased potency and selectivity for IK_S- Consequently, these compounds hold promise as useful antiarrhythmic agents, anti-ulcer agents, and anti-diarrheal agents. Furthermore, they are expected to have fewer undesirable side effects than existing antiarrhythmic drugs such as amiodarone, dofetilide, or lbutihde.

Definitions and Usage of Terms:

The following is a list of definitions for terms used herein.

"Acyl" or "carbonyl" is described as a radical which could be formed by removal of the hydroxyl moiety from a carboxyhc acid (i.e., R-C(=0)-). Preferred acyl groups include (for example) acetyl, formyl, and propionyl.

"Alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; more preferably from 2 to 8, except where indicated. Alkenyl substituents have at least one olefimc double bond (including, for example, vinyl, allyl and butenyl). "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.

"Alkoxyalkyl" is an unsubstituted or substituted alkyl moiety bearing an alkoxy moiety (i.e., -alkyl-O-alkyl). Preferred is where the alkyl has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms), and the alkoxy has 1 to 6 carbon atoms (more preferably 1 to 3 carbon atoms)

"Alkyl" is an unsubstituted or substituted saturated hydrocarbon chain radical having 1 to 15 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 1 to 4, except where indicated. Preferred alkyl groups include (for example) substituted or unsubstituted methyl, ethyl, propyl, isopropyl, and butyl. A "lower" hydrocarbon moiety (e.g., "lower" alkyl) is a hydrocarbon chain comprised of 1 to 6, preferably from 1 to 4, carbon chain atoms.

As referred to herein, "spirocycle" or "spirocyclic" or "spiro ring" refers to a cyclic moiety sharing a single atom (e.g., carbon) of another ring. Such a cyclic moiety may be carbocyclic or heterocyclic in nature. Preferred spirocyclic ring sizes include 5-7 membered rings. Preferred heteroatoms included in the backbone of the heterocyclic spirocycle include oxygen, nitrogen and sulfur. In addition, the heteroatom of the heterocycle may be alkyl- or acyl-substituted if valence allows.

"Alkylammo" is an amino radical having one (secondary am e) or two (tertiary amine) alkyl substituents (i.e., -NH-alkyl or N-(alkyl)2). For example, methylamino (-NHCH3), dimethylammo (-N(CH3)2), methylethylammo (-

N(CH₃)CH₂CH₃).

"Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, denyl, naphthyl, biphenyl and fluorenyl. Such groups may be substituted or unsubstituted.

"Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl, phenylethyl, and phenylpropyl. Such groups may be substituted or unsubstituted.

"Carbocyclic ring" is an unsubstituted or substituted, saturated or unsaturated hydrocarbon ring radical. Carbocyclic rings are monocychc or are fused, bridged or spirocyclic ring systems. Monocychc carbocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. Polycyclic carbocyclic rings contain 7 to 17 atoms, preferably from 7 to 12 atoms. Preferred polycyclic systems comprise 4-,5-,6- or 7-membered rings fused to 5-,6-,or 7-membered rings "Cycloalkyl" is a substituted or unsubstituted, saturated hydrocarbon ring radical comprising from 3 to 6 ring atoms. Examples include cyclohexyl, cycloheptyl, cyclobutyl and cyclopropyl.

"Fluoroalkyl" is haloalkyl wherein the only halogen atom contemplated is fluorine.

"Fused rings" are rings that are superimposed together such that they share two ring atoms. A given ring may be fused to more than one other ring. Fused rings are contemplated in heteroaryl, aryl and heterocycle radicals or the like.

"Halo", "halogen", or "hahde" is a chloro, bromo, fluoro or lodo atom radical. Bromo, chloro and fluoro are preferred halides.

"Haloalkyl" is branched or unbranched alkyl radical having one or several halo substitutents (i.e., -C_nH(2n-m)X(m+l)_> where n = 1 to 15 and m = 0 to 2n).

"Haloacyl" is acyl radical having one or several halo substituents (i.e., - C(=0)C_nH(2n-m)X(m+l), where n = 1 to 4, and m = 0 to 2n, e.g. COCF3, COCF2CF3, etc.

"Heterocylic ring" is an unsubstituted or substituted, saturated or unsaturated ring radical comprising at least one heteroatom (i.e., O, S, or N). Heterocyclic rings are monocychc or are fused, bridged or spirocyclic ring systems. Monocychc heterocyclic rings generally contain 4 to 9 atoms, preferably 4 to 7 atoms. Polycyclic heterocyclic rings contain 7 to 17 atoms, preferably from 7 to 12 atoms. Preferred polycyclic heterocyclic systems comprise 4-, 5-, 6- or 7-membered rings fused to 5-, 6-, or 7- membered rings.

A "pharmaceutically-acceptable salt" is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., ammo) group. Many such salts are known in the art, as described m World Patent Publication 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein). Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), phosphates, acetates, citrate and maleate salts.

"Biohydrolyzable carbamates" are carbamate derivatives of the compounds of the invention that do not interfere with the ion channel inhibitory activity of the compound, or that are readily converted m vivo by a mammal subject to yield an active ion channel blocker. A "biohydrolyzable ester" refers to an ester that does not interfere with the ion channel inhibitory activity of these compounds or that is readily converted m vivo by a mammal to yield an active ion channel blocker

"Optical isomer", "stereoisomer", "diastereomer" as referred to herein have the standard art recognized meanings (Cf, Hawley's Condensed Chemical Dictionary. 11th Ed.)

The illustration of specific esters, amides or other deπvatized forms of the Formula (A) compounds is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.

Compounds

The present compounds have a structure according to Formula (A)

R₆

wherein

(a) Ri is selected from haloalkyl, haloacyl, R7SO2R8, and NR7COR8 (preferably haloalkyl, NR7SO2R8 and NR7COR8, more preferably haloalkyl, and most preferably tπfluoromethyl, pentafluoroethyl and tπfluoroacetamido);

(b) each R2 is independently selected from hydrogen, alkyl, halo, alkoxy, and alkoxyalkyl (preferably hydrogen and halo, more preferably hydrogen);

(c) R3 is lower alkyl, or together with R4 forms a spirocycle of from 4 to 7 members (preferably methyl, ethyl, or together with R₄ spiropentyl),

(d) R4 is lower alkyl, or together with R3 forms a spirocycle of from 4 to 7 members (preferably methyl, ethyl, or together with R₃ spiropentyl);

(e) R5 is selected from hydrogen, alkyl, aryl, arylalkyl, and haloalkyl (preferably alkyl and haloalkyl, more preferably methyl, ethyl, propyl, butyl, frifluoromefhyl, and 1,1,1-trιfluorobutyl);

6 R6 is selected from alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, and alkylammo (preferably alkyl and haloalkyl, most preferably methyl, ethyl, propyl, butyl, and 1,1,1-trιfluorobutyl);

7. R7 is selected from hydrogen and alkyl (preferably hydrogen); and

8. Rδ is C -C4 haloalkyl (preferably tπfluoromethyl) Using the examples and this discussion the skilled artisan can generate a variety of compounds in a similar fashion, using the guidance of the general synthetic scheme below. These steps may be varied to increase yield of desired product. The skilled artisan will also recognize the judicious choice of reactants, solvents, and temperatures is an important component in successful synthesis. While the determination of optimal conditions, etc. is routine, it will be understood that a variety of compounds can be generated in a similar fashion, using the guidance of the schemes herein.

The starting materials used in preparing the compounds of the invention are either known, made by known methods, or are commercially available

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well with the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophihc and nucleophihc, etheπfications, esteπfication and sapomfication and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2).

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups m Organic Synthesis. Of course, ammo acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.

The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one stereoisomer (a diastereomer, epimer, or enantiomer) over another, for example by chiral starting materials, catalysts or solvents; by chromatographic means; by crystallization or distillation; or one may prepare mixtures of stereoisomers (mixtures of diastereomers, epimers, or enantiomers) at once. The present invention explicitly encompasses either single stereoisomers or mixtures thereof.

In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well. Indeed, as discussed above, with respect to preferred compounds, the 3R,4S stereochemistry is preferred over the 3S,4R racemate, which is contrary to the teachings of the prior art concerning benzopyrans.

Preparation of the compounds

General Reaction Scheme 1

T3£_0H ^"TJX"

Compounds of the present invention can be prepared via synthetic routes well- established m the literature, and outlined m Scheme 1. Reaction of appropriately substituted phenols, I, with a 3-X-alkyne II (where halo or other suitable leaving group is X, such as in a 3-chloroalkyne derivative) in the presence of an acid scavenger such as K2CO3 in a solvent such as acetone or dimethylformamide, provides the corresponding propargyl phenyl ethers III, which rearrange under appropriate thermal conditions (e.g 50°C-200°C, preferably 150°C) in the presence of an appropπate base (e.g. aniline, dimethylanihne, or preferably diethylanihne) m an organic solvent such as dimethylsulfoxide, acetone, or, preferably, dimethylformamide, to yield the corresponding 2,2-dιsubstιtuted benzopyrans IV. Alternatively, the compounds of general structure IV are arrived at by reduction of the 2,2-dιsubstιruted benzopyran-3-ones of general structure VII by the action of various reducing agents, including NaBH4, in inert solvents such as tetrahydrofuran, and subsequent dehydration by the action of, for example, para- toluenesulfonic acid. The requisite 2,2-dιsubstιtuted benzopyran-3-ones of general structure VII are prepared by either of two general methods. First, by condensation of appropriately substituted 2-hydroxyphenyl methyl ketones VI, the presence of a secondary amine, such as pyrolhdme, and under removal of H2O. See Bergmann, R. et al. "Synthesis and antihypertensive activity of 4-(l,2-dιhydro-2-oxo-l-pyπdyl)-2H-l- benzopyrans and related compounds, new potassium channel activators" J. Med. Chem Vol. 33, pp. 492-504 (1990). Second, by reaction of phenols of general structure I with acrylate derivatives VIII to provide the esters of general structure IX. Cychzation to the 2,2-dιsubstιtuted benzopyran-3-ones of general structure VII is achieved under the influence of strong Lewis or Brønsted acids, for example under the action of polyphosphoπc acid or AICI3 in inert solvents such nitromethane.

The 2,2-dιsubstιtuted benzopyrans of general structure IV are epoxidized under a variety of conditions known to those skilled in the art, for instance by the method of Jacobsen. See Lee, N.-H. et al. "Enantiomeπcally pure epoxychromans via asymmetric catalysis." Tetrahedron Letters Vol. 32(38), pp. 5055-8 (1991). The resulting epoxides X are reacted with the anion of an appropriately substituted sulfonamides XI to yield the target compounds XII. See Lohrmann, E.; Burhoff, I.; Nitscke, R. B.; et al. "A new class of inhibitors of cAMP-mediated Cl secretion in rabbit colon, acting by the reduction of cAMP-activated K⁺ conductance," Pflύgers Arch - Eur. J. Physiol.. Vol 429, 517-530 (1995). The requisite sulfonamides XI are conveniently and routinely prepared by reaction of an appropriate primary amine and an appropriate sulfonyl chloride or sulfonic acid anhydride in an inert solvent such as dichloromethane.

General Reaction Scheme 2

The preparation of compounds of the present invention which bear a sulfonamido or trifluoracetamido moiety at the R\ position are illustrated in Scheme 2. They are prepared by further elaboration of compounds XII, where R\ is NO2. Thus, according to Scheme 2, reduction of the nitro moiety with a mild reducing agent, such as stannous chloride in a hydroxyhc solvent such as ethanol, provides compounds of general structure XIII. These aniline derivatives are reacted with the appropriate acid chlorides, such as tπfluoracetyl chloride or tπfluoromethanesulfonyl chloride, m inert solvents such as dichloromethane or tetrahydrofuran, and in the presence of a scavenger amme such as tπethylamine, to provide amides of general structure XIV or XV. Conversion to the corresponding N-methyl derivatives XVI or XVII is accomplished by a routine NaH / Mel reaction sequence, m a solvent such as tetrahydrofuran

The following is a non-hmitmg list of the phenols that are employed in Scheme 1. These phenols are either obtained from commercial sources, or prepared according to literature methods:

Many of these and similar compounds are available via common commercial sources, such as Sigma- Aldπch-Fluka Chemical Company; Oakwood Products, Inc., Maybridge Chemical Company; Lancaster Synthesis; or others. The preparation of these and similar (l,l,l-tπfluoromethyl)-beaπng phenols are also described in the synthetic literature, and can be prepared with ordinary skills and techniques in the art of synthetic chemistry. Examples of these materials follow m the examples. The skilled artisan will appreciate that suitably substituted starting materials can be chosen and used to prepare the compounds of the present invention, using the information provided herein or available m the art. The following non-hmitmg examples illustrate the compounds, compositions, and uses of the present invention. Examples

Reagents and solvents are generally used as received from the commercial supplier Reactions are routinely performed under a N2 atmosphere m oven-dπed glassware Column chromatography is performed on silica gel (230 - 400 mesh; Merck) Th layer chromatography analysis (TLC) is performed on 250-μM pre-coated Merck silica gel F254 glass-backed plates. Spots are visualized under 254-nm UV light or by staining with a spray reagent consisting of 5% phosphomolybdic acid m EtOH.

Examples 1-13

The following Examples 1 through 13 are representative of compounds IH in General Reaction Scheme 1, above.

3-Methyl-3-(4-nitrophenyloxy)-but-l-yne (Example 1). To a stirred mixture of 4-nιtrophenol (0.12 mol), dry K2CO3 (0.25 mol), KI (0.21 mol), and Cul (2 4 mmol) in dry dimethyl formamide (DMF) (122 mL) under argon is added 3-chloro-3-methylbut-l-yne (0.25 mol). The reaction mixture is heated at 65 °C for 4 h. The reaction is diluted with water and extracted with 2 x 1 L of hexane. The organic extracts are pooled and filtered. The filtrate is washed sequentially with 2N NaOH, 2N HC1, and water. The organic layer is dried over anhydrous Na2Sθ4 and filtered. The filtrate is concentrated under reduced pressure to leave the title compound, which is used without further purification.

3-Methyl-3-(4-(l,l,l-trifluoromethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 4-(l,l,l-tπfluoromethyl)phenol.

3-MethyI-3-(2-nitro-4-(l,l,l-trifluoromethyI)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 2-nιtro-4-( 1,1,1 -tπfluoromethyl)- phenol.

3-Methyl-3-(3-chloro-4-(l,l,l-trifluoromethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 3-chloro-4-(l,l,l-tπfluoromethyl)- phenol.

3-Methyl-3-(3-fluoro-4-(l,l,l-trifluoromethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 3-fluoro-4-(l,l,l-tπfluoromethyl)- phenol.

3-Methyl-3-(2,3-difluoro-4-(l,l,l-trifluoromethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 2,3-dιfluoro-4-(l,l,l-tπfluoromethyl)- phenol. 3-Methyl-3-(2-chloro-4-(l,l,l-trifluoromethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 2-chloro-4-( 1,1,1 -tπfluoromethyl)- phenol. l-(3-Chloro-4-(2,2-dimethyl-2-propynyloxy)-phenyl)-2,2,2-trifluoro-l- ethanone. This compound is prepared according to Example 1 from l-(3-chloro-4- hydroxyphenyl)-2,2,2-tπfluoro- 1 -ethanone.

3-Methyl-3-(4-(2,2,2-trifluoroethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 4-(2,2,2-tπfluoroethyl)phenol.

3-Methyl-3-(4-(l,l,l,2,2-pentafluoroethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 4-(l,l,l,2,2-pentafluoroethyl)phenol.

3-Methyl-3-(3-chloro-4-(l,l,l,2,2-pentafluoroethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from l-(3-chloro-4-( 1,1, 1,2,2- pentafluoroethyl))phenol . l-(2-Fluoro-4-(2,2-dimethyl-2-propynyloxy)-phenyl)-2,2,2-trifluoro-l- ethanone. This compound is prepared according to Example 1 from 1 -(2-fluoro-4- hydroxyphenyl)-2,2,2-tπfluoro-l-ethanone.

3-Methyl-3-(2,3-dichloro-4-(l,l,l-trifluoromethyl)phenyloxy)-l-butyne. This compound is prepared according to Example 1 from 2,3 -dιchloro-4-( 1,1,1 -tπfluoromethyl)- phenol.

Examples 14-22

The following Examples 14 through 22 are representative of compounds IV in General Reaction Scheme 1, above.

3,4-Dihydro-2,2-dimethyl-6-nitro-2H-l-benzopyran (Example 14). A stirred solution of 3-methyl-3-(4-nιtrophenyloxy)-but-l-yne (0.11 mol) and N,N-dιethylanιhne (6.8 mmol) in dry DMF (108 mL) is heated at 130°C for 20 h. The reaction is chilled and poured over 1 L H2O. The aqueous mixture is extracted with 1 x 1 L and 2 x 500 mL of hexane. The organic extracts are pooled and washed successively with 2 x 1 L 2N NaOH, 1 x 1 L 2N HCl, and 1 x 1 L H2O. The organic phase is dried over anhydrous Na2Sθ4 and filtered. The filtrate is concentrated under reduced pressure to leave a solid residue which is crystallized from hexanes to give the title compound.

2,2-Dimethyl-6-(l,l,l-trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 14 from 3-methyl-3-(4-(l,l,l-tπfluoromethyl)phenyloxy)- but-1-yne. 7-Chloro-2,2-dimethyl-6-(l,l,l-trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 14 from 3-methyl-3-(3-chloro-4-(l,l,l- tπfluoromethyl)phenyloxy)-but-l-yne, followed by silica gel chromatography to separate the lsomeπc product 5-chloro-2,2-dιmethyl-6-(l,l,l-tπfluoromethyl)-2H-l-benzopyran.

5-Chloro-2,2-dimethyl-6-(l,l,l-trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 14 from 3-methyl-3-(3-chloro-4-(l,l,l- tπfluoromethyl)phenyloxy)-but-l-yne, followed by silica gel chromatography to separate the lsomeπc product 7-chloro-2,2-dιmethyl-6-(l,l,l-tπfluoromethyl)-2H-l-benzopyran.

2,2-Dimethyl-8-chloro-6-(l,l,l-trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 14 from 3-methyl-3-(2-chloro-4-(l,l,l- tπfluoromethyl)phenyloxy)-but-l-yne.

2,2-Dimethyl-6-trifluoroacetyl-2H-l-benzopyran. This compound is prepared according to Example 14 from l-(3-chloro-4-(2,2-dιmethyl-2-propynyloxy)-phenyl)-2,2,2- tπfluoro- 1 -ethanone .

2,2-Dimethyl-6-nitro-2H-l-benzopyran. This compound is prepared according to Example 14 from 3-methyl-3-(4-nιtrophenyloxy)-but-l-yne.

2,2-Dimethyl-6-(l,l,l,2,2-pentafluoroethyl)-2H-l-benzopyran. This compound is prepared according to Example 14 from 3-methyl-3-(4-( 1,1,1, 2,2-pentafluoroethyl)- phenyloxy)-but-l-yne.

2,2-Dimethyl-8-fluoro-6-trifluoroacetyl-2H-l-benzopyran. This compound is prepared according to Example 14 from l-(2-fluoro-4-(2,2-dιmethyl-2-propynyloxy)- phenyl)-2,2,2-tπfluoro-l-ethanone.

Examples 23-28

The following Examples 23 through 28 are representative of compounds X in General Reaction Scheme 1 , above

(3R,4R)-2,3-Dihydro-2,2-dimethyl-3,4-epoxy-6-nitro-2H-l-benzopyran (Example 23). A solution of commercial bleach (500 mL, 5.25% w/w) and aqueous 0.05M Na2HPθ4 (100 mL) is brought to a pH of 11.3 with 1 N NaOH. The volume is adjusted to a total of 636 mL with H2O to give a 0.55 M solution of NaOCl. A 216-mL portion of this solution is cooled to 0°C with a salt-ice bath, and vigorously stirred with a mechanical stirrer. To this is added dropwise via addition funnel a solution of 3,4-dιhydro- 2,2-dιmethyl-6-nιtro-2H-l-benzopyran (12.0 g, 58.5 mmol) and (R,R)-(-)-N,N'-bιs(3,5- ditetrabutylsahcyhdme-l,2-cyclohexanediaminomanganese III chloride (R,R-Jacobsen's catalyst, 1.34 g, 2.11 mmol) in CH2CI2 (83 mL). Care is taken to maintain the reaction temperature below 0°C. The reaction is monitored by TLC (hexane/EtOAc, 9:1). After addition is complete, vigorous stirπng is continued at 0°C for 16 h. The reaction mixture is separated and the organic layer diluted with additional CH2CI2 (200 mL), and the mixture is filtered through Cehte. The filtrate is washed with brine, dried (Na2Sθ4/Darco), filtered, and concentrated under reduced pressure. The residue is taken up in CH2θ2/hexane (1:9), slurπed on silica gel and filtered. The filtrate is concentrated under reduced pressure to provide the title compound.

(3R,4R)-2,3-Dihydro-2,2-dimethyI-3,4-epoxy-6-(l,l,l-trifluoromethyl)-2H-l- benzopyran. This compound is prepared according to Example 23 from 2,2-dιmethyl-6- (1,1,1 -tπfluoromethyl)-2H- 1 -benzopyran.

(3R,4R)-7-Chloro-2,3-dihydro-2,2-dimethyl-3,4-epoxy-6-(l,l,l- trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 23 from 7-chloro-2,2-dιmethyl-6-( 1 , 1 , 1 -tπfluoromethyl)-2H- 1 -benzopyran.

(3R,4R)-5-Chloro-2,3-dihydro-2,2-dimethyl-3,4-epoxy-6-(l,l,l- trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 23 from 5 -chloro-2,2-dιmethyl-6-( 1,1,1 -tπfluoromethyl)-2H- 1 -benzopyran.

(3R,4R)-2,3-dihydro-2,2-dimethyl-3,4-epoxy-8-fluoro-6-(l ,1 ,1- trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 23 from 2,2-dιmethyl-8-fluoro-6-( 1,1,1 -tπfluoromethyl)-2H- 1 -benzopyran.

(3R,4R)-2,3-dihydro-2,2-dimethyl-3,4-epoxy-7-fluoro-6-(l,l,l- trifluoromethyl)-2H-l-benzopyran. This compound is prepared according to Example 23 from 2,2-dιmethyl-7-fluoro-6-( 1,1,1 -tπfluoromethyl)-2H- 1 -benzopyran.

Example 29

The following Example 29 is representative of compounds XII in General Reaction Scheme 1, above. trans-(3R,4S)-N-(3,4-dihydro-3-hydroxy-2,2-dimethyl-6-nitro-2H-l-benzo- pyran-4-yl)-N-methyl-methanesulfonamide (Example 29). A mixture of sodium hydride (60% dispersion in oil; 119 mg, 2.98 mmol) in dry tetrahydrofuran (THF) (2 mL), is stirred under argon and cooled to 15°C. The mixture is treated with a solution of N- methyl-methanesulfonamide (360 mg, 2.98 mmol) in dry THF (2 mL). The reaction mixture is further chilled to 0°C, and neat trimethylsilyl chloride (0.23 mL, 1.84 mmol) is added dropwise. The reaction is allowed to warm to 15°C, and a solution of (3R,4R)-2,3- dιhydro-2,2-dιmethyl-3,4-epoxy-6-nιtro-2H-l -benzopyran (219 mg, 0.99 mmol) in dry THF (1.5 mL) is added, followed by a solution of tetrabutyl ammonium fluoride (1 M in THF, 0.99 mL). The reaction mixture is heated at 57°C for 4 h. After cooling to 20°C, the reaction is evaporated under reduced pressure. This product is partitioned between H2O (25 mL) and EtOAC (3 x 50 mL). The organic extracts are pooled, washed with H2O, and dried over anhydrous Na2Sθ4. The desiccant is filtered off and the filtrate concentrated under reduced pressure. Crystallization from MeOH/H2θ provides the title compound

Example 30

The following Example 30 is representative of compounds XIII m General Reaction Scheme 2, above. trans-(3R,4S)-N-(6-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l- benzopyran-4-yl)-N-methyl-methanesuIfonamide (Example 30). To a suspension of trans-(3R,4S)-N-(3,4-dιhydro-3-hydroxy-2,2-dιmethyl-6-nιtro-2H-l-benzopyran-4-yl)-N- methyl-methanesulfonamide (1.21 g, 3.51 mmol) in absolute EtOH (15 mL) is added SnCl₂ ^«H₂0 (11 g, 14 equivalents), and the mixture is heated at 50°C for 5 h. The reaction mixture treated with CHC1₃ (20 mL), H₂0 (20 mL), and saturated aqueous NaHC0₃ (50 mL), and then filtered through Cehte to remove precipitated tin by-products The filtrate is partitioned with ιsopropanol-CHCl₃ (1:5, 60 mL). The organic layer is dried over MgS0₄, filtered, and evaporated to yield the title compound.

Example 31

The following Example 31 is representative of compounds XV in General Reaction Scheme 2, above. trans-(3R,4S)-N-(3,4-dihydro-3-hydroxy-2,2-dimethyl-6-trifluoroacetamido- 2H-l-benzopyran-4-yl)-N-methyl-methanesulfonamide (Example 31). To an ice-cold solution of trans-(3R,4S)-N-(6-ammo-3,4-dιhydro-3-hydroxy-2,2-dιmethyl-2H-l- benzopyran-4-yl)-N-methyl-methanesulfonamιde (233 mg, 0.741 mmol) in CH₂C1₂ (4 mL) is added tπfluoroacetic anhydride (149 mg, 0.708 mmol), followed by slow addition of tπethylamme (73 mg, 0.72 mmol). The reaction is allowed to warm to ambient temperature over a period of 3.5 h. The reaction mixture is partitioned with H₂0 (4 mL), saturated NH₄CI (1 mL) and CH₂C1₂ (3 x 3 mL). The organic layers are combined, dπed over MgS0₄, and evaporated to yield the title compound.

Using General Reaction Schemes 1 and 2, the chemistry illustrated for preparing Examples 1-31, and employing the appropriately substituted sulfonamide, the following additional examples of the present invention are prepared with substantially similar results Specifically examples 32 through 74 are prepared according to General Reaction Scheme 1 and examples 75 through 86 are prepared according to Scheme 2. Re

In the following table, the R₂ substituents at positions 5, 7 and 8 of the benzopyran nucleus are all hydrogen, unless otherwise indicated. While Formula (A) and the table of substituents does not distinguish between enantiomers, both enantiomers are represented for each example.

Compositions

Compounds of this invention are useful in treating cardiac arrhythmias and/or cardiac fibrillation in humans or other mammals. Therefore, this invention relates to a method for treating a human or other mammal suffering from cardiac arrhythmia and/or cardiac fibrillation which comprises administering to said human or other mammal a safe and effective amount of a pharmaceutical composition comprising from 15-90% of a compound active ingredient, or mixtures thereof, and from 10-85% phaimaceutically-acceptable excipients.

The invention compounds can be formulated into pharmaceutical compositions for use in treatment or prophylaxis of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., latest edition.

A "safe and effective amount" of a Formula (A) compound is an amount that is effective, to reduce the frequency and severity of cardiac arrhythmias in a human subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the earner employed, the solubility of the Formula (A) compound therein, and the dosage regimen desired for the composition

In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal being treated. Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as steaπc acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glyceπne, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, including nomonic surfactants, such as the TWEENS"; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; lsoto c saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used m conjunction with the subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4.

In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, lsotomc salme, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrohdone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.

The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a Formula (A) compound that is suitable for administration to humans in a single dose, according to good medical practice. These compositions preferably contain from about 0.5 mg (milligrams) to about 500 mg, more preferably from about 1 mg to about 100 mg, more preferably from about 1 mg to about 30 mg, of a Formula (A) compound.

The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the antiarrhythmic, anti-diarrheal, or anti-ulcer activity of the Formula (A) compound. The amount of carrier employed in conjunction with the Formula (A) compound is sufficient to provide a practical quantity of material for administration per unit dose of the Formula (A) compound. Techniques and compositions for making dosage forms useful m the methods of this invention are described in the following references, all incorporated by reference herein- Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms' Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the Formula (A) compound. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known m the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; dismtegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets Capsules typically comprise one or more solid diluents disclosed above The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art

Peroral compositions also include liquid solutions, emulsions, suspensions, and the like The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth and sodium algmate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methyl paraben and sodium benzoate Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above

Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvmylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac

Compositions of the subject invention may optionally include other drug actives The compounds of the present invention can be used in combination with a number of other pharmacological agents, such as beta-blockers, calcium channel antagonists, endothehn antagonists, sodium-hydrogen exchange inhibitors, motropic agents, angiotensm-convertmg enzyme inhibitors, cholesterol-lowering agents, diuretic agents, antiplatelette, or antithrombotic therapy to reduce the frequency and severity of arrhythmic events They could also be used in combination with antnnfective agents to treat gastrointestinal ulcers The compounds of the present invention can be dosed orally or intravenously after formulation with appropriate diluents, solvents, or adsorbents

Other compositions useful for attaining systemic delivery of the subject compounds include subl gual, buccal and nasal dosage forms Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystallme cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose Glidants, lubricants, sweeteners, colorants, antioxidants and flavoπng agents disclosed above may also be included Methods of Administration

This invention also provides methods of treating or preventing cardiac aπhythmias, diaπhea, and gastric ulcers in animals, preferably a mammalian subject, by administering a safe and effective amount of a Formula (A) compound to said subject The methods of the invention are useful in treating disorders such as (for example) atrial tachycardia, atrial flutter, atπal fibrillation, ventricular tachycardia, ventricular extrasystole, ventricular fibrillation, Wolfe-Parkmson-White syndrome, Long QT Syndrome, or sudden cardiac death.

The Formula (A) compounds and compositions of this invention can be administered systemically by any method of introducing Formula (A) compound into the tissues of the body, e.g., intramuscular, intravenous, mtrapeπtoneal, subcutaneous, sublmgual, rectal, and oral administration. The Formula (A) compounds of the present invention are preferably administered orally or intravenously.

The specific dosage of inhibitor to be administered, as well as the duration of treatment, and whether the treatment is administered by the oral or intravenous route are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific Formula (A) compound used, the treatment indication, the ability of the Formula (A) compound to reach minimum efficacious concentrations in the heart or the gut, the personal attributes of the subject (such as weight), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.

Typically, for a human adult (weighing approximately 70 kilograms), from about 0.5 mg to about 500 mg, more preferably from about 1 mg to about 100 mg, more preferably from about 1 mg to about 30 mg, of Formula (A) compound are administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors listed above.

In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.

All references cited herein are hereby incorporated by reference in their entirety. As such, they illustrate the state of the art.

While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention It is intended to cover, in the appended claims, all such modifications that are withm the scope of this invention.

Claims

WHAT IS CLAIMED IS:

1. A compound having a structure according to Formula (A):

R₆

wherein

(a) Ri is selected from haloalkyl, haloacyl, -NR7SO2R8, or -NR7COR8;

(b) each R2 is independently selected from hydrogen, alkyl, halo, alkoxy, or alkoxy alkyl;

(c) R3 is lower alkyl, or together with R4 forms a spirocycle of from 4 to 7 members;

(d) R4 is lower alkyl, or together with R3 forms a spirocycle of from 4 to 7 members;

(e) R5 is selected from hydrogen, alkyl, aryl, arylalkyl, or haloalkyl;

(f) R6 is selected from alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, or alkylamino;

(g) R7 is selected from hydrogen or alkyl; and (h) R8 is C1 -C4 haloalkyl; or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof, or any other derivative which is bioconverted to Formula (A).

2. The compound according to Claim 1 , wherein:

(a) Ri is selected from C C₄ haloalkyl, C2-C₄ haloacyl, -NR7SO2R8, or NR7COR8;

(b) each R2 is independently hydrogen or halo;

(c) R3 is selected from methyl, ethyl, or together with R4 forms a carbocyclic spiro ring having from 4 to 7 ring members;

(d) R4 is selected from methyl, ethyl, or together with R3 forms a carbocyclic spiro ring having from 4 to 7 ring members;

(e) R5 is selected from C1-C4 alkyl or C1-C4 fluoroalkyl;

(f) R is selected from C1-C4 alkyl, C1-C4 fluoroalkyl, cycloalkyl or aryl;

(g) R7 is selected from hydrogen or methyl; and (h) R8 is C1-C4 fluoroalkyl.

3. The compound according to Claim 2, wherein:

(a) R\ is selected from -C4 fluoroalkyl, C2 haloacyl, -NR7SO2R8, or -NR7COR8;

(b) each R2 is independently hydrogen or halo;

(c) R3 is selected from methyl or ethyl, or together with R4 forms a carbocyclic spiro ring having from 5 or 6 ring members;

(d) R4 is selected from methyl or ethyl, or together with R3 forms a carbocyclic spiro ring having from 5 or 6 ring members;

(e) R5 is selected from C1-C4 alkyl or C -C4 fluoroalkyl;

(f) R is selected from C1-C4 alkyl, C1-C4 fluoroalkyl, cycloalkyl or aryl;

(g) R7 is selected from hydrogen or methyl; and (h) R8 is C1-C2 fluoroalkyl.

4. The compound according to Claim 3, wherein:

(a) Ri is selected from C1-C4 fluoroalkyl, C2 fluorooacyl, -NR7SO2R8, or -NR7COR8;

(b) each R2 is hydrogen;

(c) both R3 and R4 is methyl;

(d) R5 is selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

(e) R6 is selected from C1-C3 alkyl, C1-C3 fluoroalkyl, cycloalkyl or phenyl;

(f) R7 is selected from hydrogen or methyl; and

(g) R is trifluoromethyl.

5. The compound according to Claim 4, wherein:

(a) Ri is CF3, CH2CF3, CF2CF3, CF3CO, -NHCOCF3, -NCH3COCF3, or NCH3SO2CF3.

6. The compound according to Claim 5, wherein:

(e) R₆ is CH3, CH2CH3, CH2CH2CH3, CH(CH₂CH ), CF3, CH CF , CF₂CF₃, CH(CH₃)2, or CH(CF₃)2.

7. The compound according to Claim 3, wherein:

(a) Ri is selected from C1-C4 fluoroalkyl, C2 fluorooacyl, -NR7SO2R8, or -NR7COR8; (b) each R2 is hydrogen;

(c) R3 together with R4 forms a carbocyclic spiro ring having from 5 or 6 ring members;

(d) R5 is selected from C1-C3 alkyl or C1-C3 fluoroalkyl;

(e) R6 is selected from C -C3 alkyl, C1-C3 fluoroalkyl, cycloalkyl, or phenyl;

(f) R7 is selected from hydrogen or methyl; and

(g) R8 is trifluoromethyl.

8. The compound according to Claim 7, wherein:

(a) Ri is CF3, CH2CF3, CF2CF3, CF3CO, NHCOCF3, NCH3COCF3, or NCH3SO2CF3.

9. The compound according to Claim 8, wherein:

(e) R6 is CH3, CH2CH3, CH2CH2CH3, CH(CH2CH2), CF3, CH2CF3, CF2CF3, CH(CH3)2, or CH(CF₃)2.

10. A compound selected from the group consisting of : trans-(3R,4S)-N-(6-( 1,1,1 -trifluoromethyl)-3 ,4-dihydro-3 -hydroxy-2,2-dimethyl-2H- l-benzopyran-4-yl)-N-propyl-ethanesulfonamide; trans-(3R,4S)-N-(6-( 1,1,1 -trifluoromethyl)-3 ,4-dihydro-3 -hydroxy-2,2-dimethyl-2H- l-benzopyran-4-yl)-N-ethyl-ethanesulfonamide; trans-(3 R,4S)-N-(3 ,4-dihydro-3 -hydroxy-2,2-dimethyl-6-( 1,1,1 -trifluoromethyl-2H- 1 - benzopyran-4-yl)-N-methyl-benzenesulfonamide; trans-(3R,4S)-N-(3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(l , 1 , 1 -trifluoromethyl)-2H- l-benzopyran-4-yl)-N-methyl-propanesulfonamide; trans-(3R,4S)-N-(3 ,4-dihydro-2,2-dimethyl-3 -hydroxy-6-( 1,1,1 -trifluoromethyl)-2H- l-benzopyran-4-yl)-N-methyl-propane-2-sulfonamide; trans-(3R,4S)-N-(3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(l , 1 ,1 -trifluoromethyl)-2H- 1 -benzopyran-4-yl)-N-methyl-methaneulfonamide; and trans-(3R,4S)-N-(3,4-dihydro-2,2-dimethyl-3-hydroxy-6-( 1,1,1 -trifluoromethyl)-2H- 1 -benzopyran-4-yl)-N-methyl-propane-l -sulfonamide.

11. A compound having a structure according to Formula (A): wherein

(a) Ri is haloalkyl;

(b) each R2 is independently selected from hydrogen and halo;

(c) R3 is lower alkyl, or together with R4 forms a spirocycle of from 4 to 7 members;

(d) R4 is lower alkyl, or together with R3 forms a spirocycle of from 4 to 7 members;

(e) R5 is selected from alkyl or haloalkyl;

(f) R6 is selected from alkyl or haloalkyl;

(g) R7 is selected from hydrogen or lower alkyl; and (h) R8 is C1-C4 haloalkyl; or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof, or any other derivative which is bioconverted to Formula (A).

12. The compound of Claim 11 wherein

(a) Ri is CF3, CH2CF3, CF2CF3, CF3CO, NHCOCF3, NCH3COCF3, or NCH3SO2CF3.

13. The compound of Claim 12 wherein

(e) R₆ is CH3, CH2CH3, CH2CH2CH3, CH(CH CH₂), CF₃, CH₂CF₃, CF₂CF , CH(CH3)2, or CH(CF₃)2.

14. A pharmaceutical composition comprising a safe and effective amount of a compound of Claim 1 and one or more pharmaceutically-acceptable excipients.

15. The pharmaceutical composition according to Claim 14, wherein the pharmaceutically-acceptable excipients are selected from the group consisting of polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoπng agents, pharmaceutical grade dyes or pigments, viscosity agents, and mixtures thereof.

16. The pharmaceutical composition according to Claim 15 compnsmg from 15-95% of the active ingredient; 0-2% flavoπng agents; 0-50% co-solvents; 0-5% buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5% viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15% disintegrants; and 1-10% binders.

17. A pharmaceutical composition comprising a safe and effective amount of a compound of Claim 11 and one or more pharmaceutically-acceptable excipients

18 The pharmaceutical composition according to Claim 17, wherein the pharmaceutically-acceptable excipients are selected from the group consisting of polymers, resms, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoπng agents, pharmaceutical grade dyes or pigments, viscosity agents, and mixtures thereof.

19. The pharmaceutical composition according to Claim 18 comprising from 15-95% of the active ingredient; 0-2% flavoπng agents; 0-50% co-solvents; 0-5% buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5% viscosity agents, 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15% disintegrants; and 1-10% binders.

20. A method of treatment for humans or other mammals afflicted with cardiac arrhythmias and or cardiac fibrillation comprised of admmisteπng to the human or other mammal a safe and effective amount of the pharmaceutical composition of Claim 14.

21. A method of treatment for humans or other mammals afflicted with cardiac arrhythmias and/or cardiac fibrillation comprised of admmisteπng to said human or other mammal a safe and effective amount of the pharmaceutical composition of Claim 17.