EP0781273A1

EP0781273A1 - 4-(4-methanesulfonamidophenyl)butylamine derivatives with antiarrhythmic activity

Info

Publication number: EP0781273A1
Application number: EP95930837A
Authority: EP
Inventors: Jackson B. Hester, Jr.; J. Kenneth Gibson
Original assignee: Pharmacia and Upjohn Co; Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1994-09-12
Filing date: 1995-08-23
Publication date: 1997-07-02
Also published as: JPH10505829A; AU3407095A; WO1996008471A1; AU688117B2; CA2196064A1

Abstract

Methanesulfonamides are structurally depicted by formula (I), or its pharmacologically acceptable salts where R3 is a C1-7 alkyl substituted with C3-7 cycloalkyl, or a C1-10 alkyl substituted with one to eight fluorine atoms, one to three hydroxy, one to three C1-5 acyloxy or one to three C1-4 alkoxy substituents. These compounds are useful as Class III antiarrhythmic agents and are stable against rapid metabolism. Methods for treating cardiac arrhythmias with the compounds of formula (I) as well as compositions thereof are also described.

Description

4-(4-METHANESULF0NAMID0PHENYL)BUTYLAMINE DERIVATIVES WITH ANTIARRHYTHMIC ACTIVITY

BACKGROUND OF THE INVENTION

The present invention is directed toward compounds having a butyl linkage between a tertiary amine group having a substituted side chain and a methanesul- fonamide substituted phenyl. Preferably the amine side chain has a fluorine substitution. These novel methanesulfonamides prolong the effective refractory period of the myocardium, have a reduced tendancy to cause arrhythmia and are very potent and stable against metabolism. Antiarrhythmic drugs act upon the electrophysiological properties of the myocardium and conductive tissues. Typically the rhythmic contractions of the heart are dependent upon the ability of the myocardium and conductive tissues to respond to electrical impulses. When the conductivity of the heart's muscle and conductive tissue is altered by an occlusion of an artery or disease, a life threatening cardiovascular deterioration is likely. It is therefore desirable to treat the electrophysiological properties of the myocardium and conductive tissue to restore rhythmic contractions while not disrupting the electrophysiological properties further which can have the undesirous side effects.

One means for restoring rhythmic contraction is with an antiarrhythmic agent that selectively prolongs the action potential duration and concomitantly increases the refractory period of heart cells without significant effect on cardiac conduction. Such drugs are classified as Class III antiarrhythmic agents. Class III antiarrhythmics which have good bioavailability and which do not affect other circulatory parameters such as blood pressure and heart rate are continually being sought. The subject compounds are Class III antiarrhythmics which are suitable for the treatment of mammals suffering from arrhythmic disorders or disease.

Class III antiarrhythmic agents have been associated with the development of a polymorphic ventricular tachycardia (PVT) known as Torsades de Pointes. This proarrhythmic potential has limited the therapeutic utility of this class of compounds for treating arrhythmias. In an animal model it has been found that ibutilide, a compound disclosed in U.S. 5,155,268, has a diminished potential for inducing PVT (L.V. Buchanan et al., J. Cardiovascular Pharmacology 220:540 ( 1993)) although further improvement is desirous. Compounds of this invention have been found to have improved and greatly diminished potential for producing PVT in this animal model. This invention thus provides compounds which have improved safety for treating arrhythmias.

Bioavailability is another important characteristic of any drug. Unfortunately, with compounds similar to compounds disclosed in U.S. 5,155,268, bioavailability is hampered by a rapid metabolism of the amine side chain. Thus, the subject invention also seeks to solve this problem by substituting the side chain to prevent rapid metabolism and thereby increase bioavailability. Surprisingly, the subject compounds have achieved this important bioavailability property and are potent antiarrhythmics as well.

INFORMATION DISCLOSURE STATEMENT

The subject compounds are structurally related to those compounds described in European Patent No. 0164865, and PCT Publication US90/03960, which discloses intermediates useful for the preparation of the subject compounds.

European Patent Application EP 0134424 discloses quaternary ammonium salts of compounds which are isomers of the subject alkanesulfonamides.

T. K. Morgan, Jr. et al., J. Med Chem., 22, 1398 (1986) reports tertiary amine alkanesulfonamides compounds.

U.S. Patents 3,341,584 and 3,478,149 disclose sulfonamide compounds some of which can be used as intermediates for the preparation of the subject compounds. Other U.S. Patents having examples of sulfonamide containing compounds and antiarrhythmic activity are DeMarinis et al. 4,507,320, Molloy et al. 4,569,801 and 4,596,827, and Gould et al. 3,574,741.

SUMMARY OF THE INVENTION In one aspect the subject invention is directed toward a compound of Formula

I, its enantiomers or pharmacologically acceptable salts thereof.

Formula I is defined where R₃ is a C^ alkyl substituted with C_{3 7} cycloalkyl, or a CJ.J_Q alkyl, substituted with from one to eight fluorine atoms, or one to three hydroxy, one to three C_j_₅acyloxy or one to three C^alkoxy substituents. Preferred compounds are where R₃ is a C_j_₇ alkyl having one or more substituents. Preferred substituents are fluorine atoms. Representative examples are N-(4-(4-(Et-hyl(7-fluoroheptyl)amino)butyl)phenyl)methanesulfonamide; N-(4-(4-(Ethyl(6-fluoroheptyl)amino)butyl)phenyl)methanesulfonamide; and N-(4-(4-(Eι±yl(6-fluoro,6-methylheptyl)amino)butyl)phenyl)methanesulfonamide. In another aspect the subject invention is directed toward a method for treating cardiac arrhythmia in mammals comprising the administration of a therapeutically effective amount of a compound of Formula I including pharmacologically acceptable salts thereof. An effective amount is from about 0.01 to about 300 mg. Preferably, the compound is administered in a unit dosage form for oral, sublingual, transdermal or parenteral administration.

The Formula I compounds are generally prepared into pharmacological preparations or compositions for therapeutic administration to patients suffering from cardiac arrhythmia. The compounds are classified as Class III antiarrhythmic compounds which are agents that selectively prolong the action potential duration and concomitantly increase the refractory period of heart cells without serious side effects or significant effects on cardiac conduction.

DETAILED DESCRIPTION OF THE SUBJECT INVENTION

Alkanesulfonanilides which prolong the effective refractory period of the myocardium and are useful for treating cardiac arrhythmias in mammals are disclosed. The compounds of the present invention are represented by the structural Formula I, or its pharmaceutically acceptable salts. Formula I is defined where R₃ is a C η alkyl substituted with a C₃,₇ cycloalkyl, or a C^_Q alkyl, substituted with from one to eight fluorine atoms, or one to three hydroxy, one to three C _₅ acyloxy or one to three C_j^alkoxy substituents.

Typically, compounds similar to those described herein suffer from a bioavailability problem associated with rapid metabolism of the amine side chain (herein, R ). It has been discovered that substitutions on this side chain can advantageously prevent rapid metabolism and thereby increase the therapeutic utility of the compounds. It has been discovered that the subject compounds have reduced side effects, such as proarrhythmic potential and, therefore, are therapeutically preferred.

An "alkyl" is a straight or branched carbon chain containing the number of carbon atoms designated such as C_{1 4}, C_j^, C_j_₁₀, etc. A "substituted" alkyl is a straight or branched carbon chain having a hydrogen atom replaced by another chemical group such as a cycloalkyl.

An "alkoxy" is an alcohol in which the hydrogen attached to the oxygen is replaced with a straight or branched carbon chain having one to four carbons.

A "cycloalkyl" is a cyclic ring structure formed from three to seven carbon atoms. The cyclic structure may also contain an alkyl substitution wherein the total carbons are calculated to include this substitution.

"Acyloxy" is an ester of a alcohol with a carboxylic acid having from one to five carbon atoms.

"Pharmacologically acceptable salts" are acid addition salts which can be prepared by any of the art recognized means. Typical, acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, cyclohexanesulfamates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, fumarates and other pharmaceutically acceptable counter ions for amines. The Formula I compounds are used for the treatment of arrhythmia wherever a Class III antiarrhythmic drug is indicated. The compounds and compositions of Formula I are administered in a therapeutic effective amount which is an amount sufficient to control arrhythmia in the host being treated such as mammals which includes humans. Typically, the Formula I antiarrhythmic agents are used in unit dosages of from 0.01 to 300 mg in oral or injectable preparations. Preferably, the Formula I compounds are used in unit dosages of 0.001 to 10 mg/kg for administration by routes either oral, sublingual, transdermal, or parenteral such as by subcutaneous, intramuscular, or intravenous injection.

The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular arrhythmia being treated, and similar considerations.

The Formula I compounds can be formulated into typical pharmaceutical preparations for either oral or parenteral administration. For example, the Formula I compound can be formulated into a composition by admixing with any of a number of suitable pharmaceutical diluents and carriers such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like. Such formulations can be compressed into tablets or can be encapsulated into gelation capsules for convenient oral administration. A gelatin capsule suited to oral administration may contain, for example, a Formula I compound in the amount of about 0.1 to about 100 mg. Such formulation can be administered orally as often as needed depending upon the particular condition and patient being treated.

For parenteral administration a Formula I compound can be formulated for intramuscular or intravenous administration. In the case of treatment of a patient suffering from a severe cardiac arrhythmia, it may be desirable to administer the Formula I compound by intravenous infusion in order to effect a speedy conversion to a normal cardiac rhythm. Such normal condition can then be maintained by oral administration. The compositions of the present invention may also include sustained release oral dosage forms and controlled release dosage forms by which the effect of the dosage is through the skin. Such compositions are those known to an ordinary skilled artisan or can be ascertained by ordinary experimentation from known compositions such as creams, gels, pastes or liquids. Typical transdermal compounds are polyethylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate.

The Formula I compounds can be combined with other antiarrhythmic agents having the same or different mechanisms of action. For example, combinations may include, Class I antiarrhythmic agents, such as quinidine, tocainide, lidocaine or the like; Class II antiarrhythmic agents, such as, propranolol, sotalol, atenolol or the like; Class III antiarrhythmic agents such as clofilium, sotalol, amiodarone and meobentine; and Class IV antiarrhythmic agents such as verapamil or diltiazem.

Formula I compounds as shown in Examples 1 and 2 are prepared as described. Other forms can be prepared by starting with suitable starting materials as described in PCT publication US90/03960, European Patents 0 164 865 and 0 233 051, U.S. Patents 3,341,584, 3,478,149, all herein incorporated by reference.

The Formula I compounds were evaluated for electrophysiological activity in an isolated, perfused rabbit cardiac tissue system. The method used was as follows: New Zealand White rabbits of either sex (1.5-2.0 kg) were anesthetized and their hearts removed. The heart was immersed in ice cold perfusate while the right atria (RA), papillary muscles (PAP), and right ventricular muscle strips (RV) were isolated. The perfusate was continuously oxygenated with 95% oxygen and 5% carbon dioxide and contained the following in mM concentrations: NaCl 118.0; KC1 5.4; NaHCOg 25.0; MgCl₂ 1.2; KH₂PO₄ 1.0; CaCl₂ 2.4; glucose 110.0 and pyruvic acid 2.0. During hypoxic conditions the perfusate was exposed to a mixture of 83% nitrogen, 10% carbon dioxide and 7% oxygen. The pH during normoxia was approximately 7.4 and dropped to approximately 7.2 during hypoxic conditions. The tissues were individually mounted on a plexiglass holder containing platinum stimulating electrodes and suspended in a 100 ml bath maintained at 30°C by a circulating heat pump. All tissues were attached by silk suture to a force- displacement transducer and a tissue-dependent preload of 500-1000 mg was applied. RA were allowed to contract spontaneously. RV and PAP were stimulated at 2X threshold with 4 msec rectangular pulses at a frequency of 1 and 3 Hz. (Effective refractory period measurements percent increment over control are ERP1 and ERP3, conduction time measurements are CT1 and CT3). Between measurements those tissues were stimulated at a resting pace of 2 Hz. Each tissue served as its own baseline control and was allowed an equilibration period of two hours prior to experiments. During this period the perfusate was changed every 10- 15 minutes. Working solutions of the drugs were prepared by dissolving the drugs in distilled water and one drop of NaOH/ml to aid in dissolution (pH 9.4).

Measurements were made on each set of tissues after exposure to 10^" , 10 , or 10 M drug for 15 minutes; and 10^"5M drug under hypoxic conditions for 15 minutes. Automaticity (RATE), force of contraction (FOC) and threshold were measured directly on a polygraph. The ERP of cardiac tissues by definition is the longest coupling interval between the basic drive (SI) and the premature impulse (S2) that fails to propagate through the tissue. The S2 stimulus was introduced after every eighth SI which allowed time for stabilization of refractoriness. Refractory period measurements were made via a digital timing circuit. The limit of resolution for these refractory period measurements was approximately 6 msec. Conduction time measurements (CT) were recorded directly in msec by gently placing a teflon-coated silver bipolar electrode against the endocardial surface of the RV strip with the resulting electrocardiogram displayed on an oscilloscope. An increase in CT is equivalent to a decrease in conduction velocity.

Examples of Formula I compounds evaluated in this manner are collected in Table I. A measure of the class III antiarrhythmic activity of these compounds is indicated by the percent increase in the effective refractory period of rabbit papillary muscle determined at pacing rates of 1 and 3 Hz (ERP_j and ERP₃). The corresponding data for ibutilide, a structurally similar compound of U.S. Patent 5,155,268 is shown for comparison. Corresponding data for a comparative compound (where the corresponding R₃ position is (CH₂)₆CH₃) disclosed in U.S. Patent 4,569,801 as formulation 5, Col. 15 is shown as Formula M (MoUoy). Corresponding data for another comparative compound (where R₃ is a fluorine substituted alkyl, (CH₂)gCH(F)CH₃), but contains an alkenyl linkage between the amine and alkanesulfonamide substituted phenyl) disclosed in PCT US90/03960 is shown as Formula H (Hester).

TABLE 1

ERP^ c ERPg' »*

Example # β₃ (SE)¹ (SE)¹

1 (CH₂)₇F 29.5 (5.4) 30.4 (1.3)

2 (CH₂)₅CH(F)CH₃ 50.1 (9.4)³ 29.2 (8.5)³

Formula H² (CH₂)₅CH(F)CH₃ 35.5 (7.02) 19.2 (2.9)

Ibutilide² (CH₂)₆CH₃ 18.0 (4.1) 15.8 (2.0)

Formula M² (CH₂)₆CH₃ 28.3 (14.1) 19.2 (2.9)

percent increase in the effective refractory period over control values measured at a drug concentration of 10 M and a pacing rate of 1 Hz percent increase in the effective refractory period over control values measured at a drug concentration of 10^" M and a pacing rate of 3 Hz

1 Standard error of the mean 2 Not a compound of the invention

Data for a drug concentration of 10^" M

TABLE 2

Examole # fig PVT(%) In Vitro Stability

1 (CH₂)₇F 6 1

3 (CH₂)₅CF(CH₃)CH₃ 0 3.2

Formula H² (CH₂)₅CH(F)CH₃ 75 3.0

Formula M² (CH₂)₆CH₃ 6 0.12

Table 2 shows data collected from Examples of the invention as compared to structurally close compounds H (Hester) and M (Molloy). The PVT data is the percentage of rabbits that demonstrated polymorphic ventricular tachycardia following exposure to the drug. In vitro stability is a measure of the metabolic stability of the drug when exposed to pooled human microsomes. The value represents the ratio of disappearance of a control (an enantiomer of Ibutilide) from a microsome incubation relative to the rate of disappearance of the drug. The value is inversely proportional to stability, therefore a small number indicates that the drug is rapidly metabolized and is unstable.

Formulas 1, 2 and 3 show good to excellent resistance to PVT with very good stability. "H" shows poor resistance to PVT but good stability and "M" shows good resistance to PVT but poor stability.

Example 1 N-(4-(4-(Ethyl(7-fluoroheptyl)amino)butyl)phenyl) methanesulfonamide

Step I. A mixture of 34.32 g (0.133 mol) of 4-((methanesulfonyl)amino)- benzenebutanoic acid (U.S. 5,155,268) and 24.74 ml (0.1775 mol) of triethylamine in 1500 ml of THF was stirred, under nitrogen for 5 minutes, cooled in an ice-2- propanol bath (-10°C) and treated dropwise during 10 minutes with 24.24 ml (0.1775 mol) of isobutyl chloroformate. This mixture was stirred at 0°C for 2 hours and then treated, dropwise during 25 minutes, with a solution of triethylamine (27.74 ml, 0.1775 mol) in 100 ml of 2.0 M ethylamine (0.2 mol) in THF. The mixture was kept at 5°C for 3.5 hours and concentrated in vacuo. The residue amounted to 40.8 g of an oil which crystallized on standing. It was recrystallized from EtOAc to give 2.68 g, mp 122-123°C and 12.71 g, mp 118-120°C of N-ethyl-4- ((methanesulfonyl)amino)benzenebutanamide.

Anal. Calc'd for C, 54.90; H, 7.09; N, 9.85; S, 11.28. Found: C, 54.85; H, 7.03; N, 9.84; S, 11.30.

Step II. To a stirred, ice cold suspension of 2.9 g (76.3 mmol) of lithium aluminum hydride in 68 ml of THF, under nitrogen, was added, dropwise during 70 minutes, a solution of 9.88 g (34.7 mmol) of the product from Step I in 200 ml of THF. The mixture was warmed to ambient temperature and kept for 1 hour; it was then refluxed for 4.5 hours and kept at ambient temperature for 18 hours. The mixture was cooled in an ice bath and treated, dropwise with 125 ml of a saturated aqueous solution of potassium sodium tartrate. This mixture was stirred 1 hour at ambient temperature and extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO₄) and concentrated to give 7.07 g of crude product which was crystallized from acetonitrile to give 6.03 g (64.2%) of N-(4-(4-(ethylamino)butyl)- phenyl)methanesulfonamide, mp 110-111°C.

Step III. A stirred mixture of 3.51 g (0.013 mol) of the product from Step II, 3.0 g (0.0152 mol) of a l-bromo-7-fluoroheptane (see, PCT/US90/03960, Ex. 32) and 2.71 g (0.0323 mol) of sodium bicarbonate in 120 ml of acetonitrile was refluxed, under nitrogen for 24 hours and kept at ambient temperature for 48 hours. Additional 1- bromo-7-fluoroheptane (0.4 g) was added and the mixture was refluxed for 3 hours and kept at 75°C for 18 hours. It was then concentrated in vacuo. The residue was mixed with ice water and extracted with CH₂C1₂; the extracts were washed with water and brine and concentrated to give 3.18 g of crude product. This was chromatographed on silica gel with 5% MeOH - 0.25% NH₄OH - CHClg to give 2.38 g of the titled product, an oil. The high resolution mass spectrum had M⁺ at m/z 386. Theory for C₂₀H₃₅FN₂O₂S: 386.2403; Measured: 386.2395. (Formula I where R₃ is -(CH₂)₆CH₂F).

Example 2 N-(4-(4-(Ethyl(6-fluoroheptyl)amino)butyl)phenyl)- methanesulfonamide Step I. A solution of 6-hydroxy heptanoic acid, ε lactone (see, PCT/US90/03960, Ex. 5) (18.94 g, 0.148 mol) in 65 mL of absolute EtOH was treated with 0.8 mL of cone. H₂SO₄, stirred at room temperature for 7 hours and concentrated in vacuo. The residue was treated with ice and neutralized with dilute NaHCO₃. The aqueous mixture was extracted with Et₂O and the extracts were washed with water and then brine. The pooled extract was dried (MgSO₄) and concentrated to give 24.38 g of crude product. This was combined with the product from a previous reaction and distilled to give 18.45 g, bp 96°C (2.2 mm Hg) and 6.73 g, bp 91°C (0.8 mm Hg) of ethyl 6-hydroxyheptanoate.

Step II. A solution of the product from Step I (18.4 g, 0.106 mol) in 200 mL of CH₂C1₂, under nitrogen, was cooled to -72°C in a dry ice-acetone bath and treated dropwise with a solution of 30 mL (0.225 mol) of EtgNSFg (DAST) in CH₂C1₂ (195 ml) over 1 hour. The mixture was stirred at -72°C for 1 hour and then for 2 hours while the mixture was allowed to warm to 5°C (by periodic addition of acetone to the bath). The mixture was maintained at 5°C for 15 minutes then poured into a mixture of 600 mL of 10% Na₂COg and 200 mL of ice with vigorous swirling (foaming). The pH of the resulting aqueous mixture was 7. This was extracted with Et^O; the extracts were washed with water and brine, dried (MgSO ) and concentrated. The residue was distilled to give 7.16 g (38.5%) of ethyl 6- fluoroheptanoate, bp 76-78° (5.8 mm Hg): NMR (CDClg) δ 1.26 (m, 4.5H), 1.35 (d, 1.5H), 1.57 (m, 6H), 2.32 (t, 2H), 4.13 (q, 2H), 4.57, 4.72 (m's, 1H).

Step III. To a mixture of 3.46 g (0.096 mol) of LiAlH₄ in 200 mL of EtgO, under N₂, at 4°C was added a solution of the product from Step II (10.4 g, 0.059 mol) in 35 mL of Et^O over 45 minutes. The mixture was stirred in the cold for 15 minutes and allowed to warm to room temperature over 100 minutes. The mixture was cooled in an ice bath and treated dropwise during 40 minutes with 35 mL of saturated aqueous Na₂SO₄; 200 mL more Et_jO was added and after stirring at ambient temperature for 15 minutes the mixture was filtered through a pad of Na₂SO₄. The filter cake was washed well with Et^O and the filtrate was concentrated in vacuo. The residue was distilled to give 4.8 g (60.7%) of product, bp 85-87°C (9.2 mm Hg), which by NMR was slightly contaminated by an alkene, and 0.58 g (7.3% of clean product, 6-fluoro-l-heptanol): bp 85-87°C (9.2 mm Hg); NMR (CDClg) δ 1.27, 1.35 (d's, 3H), 1.55 (m, 9H), 3.65 (t, 2H), 4.58, 4.73 (m's, 1H).

Step IV. A solution of triphenylphosphine (10.32 g, 0.0393 mol) and the product from Step III (4.8 g, 0.0358 mol) in 75 mL of benzene, under nitrogen, was cooled in an ice bath and treated, in portions over 40 minutes, with 7.0 g (0.0393 mol) of N- bromosuccinimide. The mixture was stirred in the cold for 20 minutes and at ambient temperature for 2.5 hours. This mixture was poured into 250 mL of pentane, a precipitate was filtered off and the filtrate was concentrated at ambient temperature in vacuo. The residue was treated with 300 mL of pentane, the mixture was cooled, a solid was filtered off and the filtrate was concentrated to 100 mL. This was cooled and a solid was filtered off. The filtrate was concentrated at ambient temperature in vacuo. The residue was treated with 200 mL of Et^O and the solution was washed with 5% Na₂S₂O₃, 0.5N NaOH and then brine, dried (MgSO₄) and concentrated in vacuo at ambient temperature to give 6.6 g (93.6%) of l-bromo-6-fluoroheptane: NMR (CDClg) δ 1.22, 1.28 (d's, 3H), 1.57 (m, 6H), 1.88 (m, 2H), 3.42 (t, 2H), 4.57, 4.73 (m's, 1H).

Step V. To a stirred mixture of 1.11 g (4.11 mmol) of N-(4-(4- (ethylamino)butyl)phenyl)methanesulfonamide (as prepared in Example 1, Step II) in acetonitrile (35 ml), under nitrogen was added 0.9 g (4.57 mmol) of l-bromo-6- fluoroheptane, the product from Step IV, and 0.77 g (9.14 mmol) of sodium bicarbonate. The mixture was refluxed for 22 hours, cooled and concentrated in yacjlQ. The residue was mixed with water and extracted with EtOAc. The extracts were washed with water and brine, dried (MgSO₄) and concentrated in vacuo to give 1.59 g of crude product. This was chromatographed on silica gel with 5% MeOH - 0.25% NH₄OH-CHCl₃ to give 0.94 g of the titled product. The high resolution FAB mass spectrum had M+H⁺ at m z 387. Theory for C₂₀H₃₆FN₂O₂S: 387.2481; measured 387.2483. (Formula I, where Rg is -(CH₂)₅CH(F)CHg.

Example 3 N-(4-(4-(Ethyl(6-fluoro-6-methylheptyl)amino)butyl)phenyl) methanesulfonamide A stirred solution of 2.0 g (0.0074 mol) of N-(4-(4-(ethylamino)butyl)phenyl)- methanesulfonamide (as prepared in Example 1, step II) in acetonitrile (64 ml) was treated with 1.72 g (0.00814 mol) of l-bromo-6-fluoro-6-methylheptane (see Example 3, Step V) and 1.24 g (0.0148 mol) of sodium bicarbonate and refluxed undemitrogen for 17.5 hours. The mixture was cooled, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 4% MeOH-0.4% NH₄OH - CH₂C1₂. A solution of the resulting product in ETOAc was washed with dilute NaHCOg and brine, dried (17g SO ) and concentrated to give 2.33 g (78.6%) of the titled product. The high resolution FAB mass spectrum had 17 + H⁺ at m z 401. Theory for C₂₁H₃₈FN₂O₂S:401.2638; measured 401.2645. (Formula I, where R₃ is - (CH₂)₅C(CH₃)₂F).

Claims

CLAIMS 1. A compound of Formula I

or pharmacologically acceptable salts thereof wherein:

Rg is a C_1-7 alkyl substituted with a C₃_₇ cycloalkyl, or a alkyl substituted with one to eight fluorine atoms, one to three hydroxy, one to three C^₅ acyloxy or one to three C^ alkoxy substituents.

2. The compound of Claim 1 where R₃ is a C_j_₁₀ alkyl substituted with one to eight fluorine atoms.

3. The compound of Claim 1 which is: a) N-(4-(4-(Ethyl(7-fluoroheptyl)aιn o)butyl)phenyl)methanesulfonamide; b) N-(4-(4-(Ethyl(6-fluoroheptyl)amino)butyl)phenyl)methanesulfonamide; and c) N-(4-(4-(Ethyl(6-fluoTO,6-meιΛy eptyl)amino)butyl)phenyl)methanesulfonamide.

4. The use of a compound of Claim 1 for preparing a medicament for treating cardiac arrhythmia in patients by administering a therapeutically effective amount of a compound of Formula I or pharmacologically acceptable salts thereof.

5. The use of Claim 4 where said effective amount is from about 0.01 to about 300 mg.

6. The use of Claim 4 where said compound is in a unit dosage form for oral, sublingual, transdermal or parenteral administration.