MXPA97005192A - (s) - antiarrhythmic banants of metansulfonami - Google Patents

Abstract

The present invention relates to the (S) -enantiomeric methanesulfonamides are structurally illustrated by Formula I: or their pharmacologically acceptable salts, wherein R 3 is a C 1-9 alkyl substituted with a fluorine atom. These compounds are useful as Class III antiarrhythmic agents without the undesirable side effect of polymorphic ventricular tachycardia (PVT) and are stable against accelerated metabolism. The methods for treating cardiac arrhythmias with the compounds of Formula I as well as the compositions of the same are also described.

Description

(S) - ANTIARRHYTHMIC BINDERS OF METALSULFONAMIDES BACKGROUND OF THE INVENTION The present invention is directed to ethanesulfonamides (S) -enantiomeric selected, characterized by a hydroxyalkyl linkage between a tertiary amine group having a substituted side chain and a phenyl substituted with methanesulfonamide, useful as Class III antiarrhythmics. These novel enantiomeric methanesulfonamides prolong the effective refractory period of the myocardium and are very potent and stable against metabolism. More importantly, these Class III antiarrhythmic compounds do not have the undesirable side effect of producing polymorphic ventricular tachycardia ("PVT"). The antiarrhythmic drugs act on the electrophysiological properties of the myocardium and conductive tissues. Typically, rhythmic contractions of the heart depend on the ability of the conductive and myocardial tissues to respond to electrical impulses. When the conductivity of cardiac muscle and conductive tissue is altered by an occlusion of an artery or disease, life-threatening cardiovascular deterioration is very likely. It is therefore desirable to treat the electrophysiological properties of the myocardium and conductive tissue to restore rhythmic contractions. A means to restore rhythmic contraction is with an antiarrhythmic agent that selectively prolongs the potential duration of action and concomitantly increases the refractory period of the heart cells without the significant effect on cardiac conduction. Such drugs are classified as Class III antiarrhythmic agents. We are continuously looking for Class III antiarrhythmics which have good bioavailability and which do not affect other circulatory parameters such as blood pressure and heart rate. The subject compounds are Class III antiarrhythmics, which are suitable for the treatment of mammals suffering from arrhythmic disorders or disease. Unfortunately, Class III antiarrhythmic agents are intended to produce PVT or torsades de pointes, which is a drug-induced arrhythmia, in a percentage of patients treated with these agents. This potentially lethal arrhythmia represents a disadvantage for this class of antiarrhythmic agents. Surprisingly, it has been found that the compounds of the present invention, although they are powerful Class III antiarrhythmics, do not cause PVT in an animal model for this arrhythmia. This is a discovery in the preparation of a Class III antiarrhythmic without a serious lateral effect of PVT. Bioavailability is an important characteristic in any drug. Unfortunately, with compounds similar to the subject compounds such as those described in U.S. 5,155,268, the bioavailability is hindered by an accelerated metabolism of the amine side chain. The object of the invention solves this problem, as previously described in PCT WO 91/01299, substituting the side chain with at least one fluorine atom to avoid accelerated metabolism and thereby increasing bioavailability.

DECLARATION OF INFORMATION DESCRIPTION The subject compounds are generally related to those compounds described in European Patent No. 0164865, which can be used as intermediates for the preparation of the subject compounds; and PCT WO 91/01299, which does not disclose the advantageous S-enantiomeric form of the subject compounds. European Patent Application EP 0134424 discloses quaternary ammonium salts of the compounds which are isomers of the target alkanesulfonamides.

T.K. Morgan, Jr. et al., J. Med. Chem., 21, 1398 (1986) reports compounds of tertiary amine alkan sulfonamides. U.S. Patents 3,341,584 and 3,478,149 describe sulfonamide compounds some of which may be used as intermediates for the preparation of the subject compounds. Other US patents that have examples of sulfonamide-containing compounds and antiarrhythmic activity are 4,507,320 of DeMarinis et al., 4,569,801 and 4,596,827 of Molloy et al. and 3,574,741 to Gould et al.

BRIEF DESCRIPTION OF THE INVENTION In one aspect the subject invention is directed towards a compound of Formula I, wherein the carbon of asymmetric alcohol has the absolute configuration (S), its enantiomers to other asymmetric carbons or their pharmacologically acceptable salts.

Formula I is defined wherein R3 is an alkyl of C-, g substituted with a fluorine atom. In another aspect the subject invention is directed towards a method of treating cardiac arrhythmia in mammals comprising administering 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 compounds of Formula I are generally prepared in pharmaceutical preparations or compositions for therapeutic administration to patients suffering from caryotic arrhythmia. The compounds are classi as Class III antiarrhythmic compounds, which are agents that selectively prolong the potential duration of action and concomitantly increase the refractory period of cardiac cells without significant effects on cardiac conduction. Advantageously, Formula I does not cause PVT.

DETAILED DESCRIPTION OF THE INVENTION OBJECT The (S) -enantiomeric alcansulfonanilides are described, which preface the effective refractory period of the myocardium and are useful for treating cardiac arrhythmias in mammals without the lateral effect of PVT. The compounds of the present invention are represented by the structural Formula I, or their pharmaceutically acceptable salts. Formula I is defined wherein R3 is an alkyl of -L.g substituted with a fluorine atom. Typically, compounds similar to those described herein suffer from the undesirable side effect of PVT, which is eliminated by using the (S) -enantiomer preparation. Bioavailability is also increased due to substitutions on the side chain, which advantageously prevent accelerated metabolism and therefore increase the therapeutic usefulness of the compounds. An "alkyl" is a straight or branched carbon chain containing the number of carbon atoms designated such as C1_4 # C1_5, C1_1Q, etc. A "substituted" alkyl is a straight or branched carbon chain having a carbon atom. hydrogen replaced by another chemical group such as a fluorine atom "Pharmacologically acceptable salts" are acid addition salts which can be prepared by any means recognized in the art Typical acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, cyclohexansulfamates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, furates and other pharmaceutically acceptable counterions for amines The compounds of Formula I are used for the treatment of arrhythmia, when a Class III antiarrhythmic drug is indicated.The compounds and compositions of Formula I are a administered in a therapeutically effective amount, which is an amount sufficient for the control of the arrhythmia in the host being treated such as mammals which include humans. Typically, the antiarrhythmic agents of Formula I are used in unit doses of 0.01 to 300 mg in oral or injectable preparations. Preferably, the compounds of Formula I are used in unit doses of 0.001 to 10 mg / kg for oral, sublingual, transdermal or parenteral administration such as by subcutaneous or intravenous injection. The particular dose of the compound administered according to this invention, will be determined, of course, by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular arrhythmia that is being treated, and similar considerations. The compounds of Formula I can be formulated into typical pharmaceutical preparations for either oral or parenteral administration. For example, the compound of Formula I can be formulated into a composition by mixing it with any of a number of suitable pharmaceutical carriers and diluents such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like. Such formulations can be compressed into tablets or encapsulated in gelation capsules for convenient oral administration. A gelatin capsule suitable for oral administration may contain, for example, a compound of Formula I in the amount of about 0.1 to about 100 mg. Such a formulation can be administered orally frequently as needed depending on the particular condition and the patient being treated. For parenteral administration, a compound of Formula I 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 compound of Formula I by intravenous infusion to effect a rapid conversion to a normal heart rate. Such a normal condition can then be maintained by means of oral administration. The compositions of the present invention can also include sustained release oral dosage forms and controlled release dosage forms by which the effect of the dose is through the skin. Such compositions are those known to one skilled in the ordinary art or can be investigated by ordinary experimentation with known compositions such as creams, gels, pastes or liquids. Typical transdermal compounds are polyethylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate. The compounds of Formula I 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 I antiarrhythmic agents such as chlorophyll, sotalol, amiodarone and meobentin; and Class IV antiarrhythmic agents such as verapamil or diltiaze.

The compounds of Formula I, as shown in Examples 1, 2 and 3, are prepared as follows. Examples of suitable starting materials are described in European Patents 0 164 865 and 0 233 051, US Patents 3,341,584, 3,478,149 all incorporated herein by reference. According to Scheme I, in Stage I, (4-methanesulfonylamino) -gamma-oxobenzenebutanoic acid (II, prepared as described in EP 164 865) are converted to N-ethylamide (III). Reagents that form the standard amide, such as dicyclohexylcarbodie ida or preferably isobutyl chloroformate, can be used for this purpose. In Step II the ketone of III is reduced with the chiral (-) -B-chlorodiisopinocanphenylborane reagent in tetrahydrofuran. The reaction is carried out below 0 ° C and preferably -25 to -35 ° C. A non-aqueous preparation is used to facilitate the isolation of the water-soluble product. The (S) - (-) enantiomer of the chiral alcohol is obtained. The purification of this alcohol by means of recrystallization from acetonitrile, methanol, ethanol, e-r-butylmethylether or mixtures thereof with high enantio purity. In Step III the amide of IV is reduced with sodium hydride bis- (2-methoxyethoxy) aluminum in tetrahydrofuran at 24 ° C. A neutral non-aqueous preparation is used to facilitate the isolation of the water-soluble product (V). The alkylation of V with appropriately substituted alkyl bromides (R3CH2Br) to give the compounds (I) of this invention is carried out in Step IV. The preferred conditions for this reaction employ acetonitrile as the solvent and the slightly basic sodium bicarbonate to neutralize the hydrogen bromide generated by the reaction. The reaction is usually carried out at the reflux temperature (81 ° C).

SCHEME 1 fibfiiJ Stage II OH CHgSOgNH / 7 - £ - CH2-CH2-C-NHC2H5"H IV O OH R3CH2Br = 2 2 2 2 5 Stage IV H The compounds of Formula I were evaluated for electrophysiological activity in a rabbit heart tissue system perfused, isolated. The method is used as follows: New Zealand White rabbits of indistinct sex (1.5-2.0 kg) were anaesthetized and their hearts were removed. The heart was immersed in ice cold perfusion solution while the right atrium (RA), papillary muscles (PAP) and right ventricular (RV) muscle strips were isolated. The prefusion solution is continuously oxygenated with 95% oxygen and 5% carbon dioxide and contains the following concentrations in mM: NaCl 118.0; KCl 5.4; NaHC03 25.0; MgCl2 1.2; KH2P04 1.0; CaCl2 2.4; glucose 110.0 and pyruvic acid 2.0. During hypoxic conditions the perfusion solution was exposed to a mixture of 83% nitrogen, 10% carbon dioxide and 7% oxygen. The pH during the normoxyá was approximately 7.4 and the dripping at approximately 7.2 during the hypoxic conditions The tissues were mounted individually on a plexiglass holder containing platinum stimulating electrodes and suspended in a bath of 100 ml maintained at room temperature. 30 ° C by means of a circulating heat pump All the tissues were fixed by means of a suture to a force displacement transducer and a tissue-dependent preload of 500-1000 mg was applied. spontaneously, RV and PAP were stimulated at a threshold of 2X with rectangular pulses of 4 milliseconds at a frequency of 1 and 3 Hz. (The increase in percent of the measurements of the effective refractory period over the control are ERP1 and ERP3, the The conduction time of the measurements are CT1 and CT3.) Among the measurements those tissues were stimulated at a repeating rate of 2 Hz. Each tissue served as its own line control. base and was left in an equilibrium period of two hours before the experiments. During this period, the perfusion solution was changed every 10-15 minutes. The drug preparation solutions were prepared by dissolving the drugs in distilled water and one drop of NaOH / ml to aid in the dissolution (pH of 9.4).

Measurements were made on each set of tissues after drug exposure at 10"7, 10 ~ 6 or 10" 5 M for 15 minutes; and the drug at 10 ~ 5 M under hypoxic conditions for 15 minutes. Automaticity (RATE), contraction force (FOC) and the threshold were measured directly on a polygraph. The ERP of cardiac tissues is by definition the longest coupling interval between the basic impulse (SI) and the premature impulse (S2) that does not propagate through the tissue. The stimulus S2 was introduced after every eight SI, which allows time for the stabilization of resistance to treatment. The measurements of the refractory period were made by means of a digital chronometer circuit. The resolution limit for these refractory period measurements was approximately 6 milliseconds. The conduction time (CT) measurements were recorded directly in milliseconds by carefully placing a silver bipolar electrode coated with Teflon against the endocardial surface of the RV strip with the resulting electrocardiogram exposed on an oscilloscope. An increase in CT is equivalent to a decrease in driving speed. Examples of the compounds of Formula I evaluated in this form 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 the papillary muscle of rabbit determined in 1 and 3 Hz rhythm velocities (ERP-j_ and ERP3). The corresponding data for ibutiluro, a compound of the U.S. Patent 5,155,268 is shown for comparison. The compounds of Formula I were evaluated for their ability to produce early posterior depolarizations (EAD) and poly orphic ventricular tachycardia (PVT) in rabbits treated with ethoxamine. The method used was as follows: Male New Zealand White rabbits (2.5 - 3.5 kg) were pretreated with subcutaneous morphine sulfate (5 mg / kg) 30 minutes before anesthesia. Anesthesia is induced by the infusion of a-chloralose (90-120 mg / kg) through a marginal ear vein for a period of 20 to 30 minutes. A tracheotomy was performed and the rabbit was breathed in ambient air (5-6 cc / kg) using a small animal ventilator (Columbus Instruments, Columbus, OH). The respiration rate, and the variable volume were adjusted, and supplemental oxygen was administered to maintain the aiterial blood gases and the pH within the normal physiological ranges. Catheters were placed in a jugular vein and carotid artery for administration of drugs, and measurement of arterial blood pressure, respectively. A 4 French monophasic action potential catheter was introduced through a jugular vein to monitor the duration of the right ventricular single phase action potential which was measured at a 90% polarization (MAPDg01). experiments, a main ECG II and arterial blood pressure All records were obtained on a multi-channel recorder (Gould ES 2000, Cleveland, OH) and the experiments were recorded continuously on an FM magnetic tape (TEAC 501, Montebello, CA) for subsequent reproduction and analysis After the experimental preparation, the rabbits were allowed to equilibrate for 10 minutes before baseline measurements of cardiac velocity, aortic blood pressure, and QTc interval were made. equilibrium, monophasic action potentials were monitored and the catheter was adjusted to produce action potentials with an amplitude After the baseline measurements, methoxamine agonist was infused at a rate of 10 μg / kg / minute in an infusion volume of 12.0 ml / h. After 15 minutes of methoxamine administration, intravenous infusion of saline (vehicle control) or a Class III agent began. All agents were administered as a continuous infusion over a period of 1 hour. The measurement of heart rate, aortic blood pressure, QTc interval (as defined in the following) and MAPD90 were repeated at various points in time during drug administration to provide dose-response relationships. QTc and MAPD90 were also monitored to ensure that the maximum class III effects on these parameters had been achieved. The total cumulative dose in the first incidence of PVT was also measured. Repolarization arrhythmias were characterized just after the depolarizations and extrasystoles during repolarization, which produced extrasystoles in the main ECG II. The PVT was considered to occur if 3 or more repetitive extrasystoles are closely coupled with a QRS morphology of torsion or twist. Methoxamine HCl and α-chloralose were purchased from Sig a Chemical Company, St. Louis, MO. Morphine sulfate was obtained from Eli Lilly Co., Indianapolis, IN. The QT intervals were corrected for changes in heart rate using the formula QTc = QT / R-R square root interval. EADs were compared between treatment groups at stable, single-phase action potential amplitudes (APA) and reported as a percent of APA.

Examples of the compounds of Formula I evaluated in this manner are collected in Table II. A measurement of the antiarrhythmic activity. Class III is indicated by an increase in QTc and MAPD9Q. The proarrhythmic potential is indicated by the incidence and magnitude of the EAD and the ratio of the incidence of PVT to the total number of animals tested. The corresponding data for ibutiluro, a compound of the United States Patent ,155,268 and the racemic forms of Examples (R, S) (compounds of WO 91/01299 PCT) are shown for comparison. TABLE 1 ERP, * ERPj **? Jt rrfio n &3 rsev (SB.Y 1 (CH2) 3-CH2F 43.5 (18.5) 26.1 (21.3) 2 (CH2) 4CH (P) CH3 30.7 (8.8) '8.7 (8.9) 3 (CH2) 4C (CH3) 2F 21.4 (3.9) 25.4 (13.7) Ibutiluro2 (CH2) gCHj 18.0 (4.1) 15.8 (2.0) * percent increase in the effective refractory period over the control values measured at a drug concentration of 10"5M and a rate of 1 Hz rhythm ** percent increase in the effective refractory period over the measured control values at a drug concentration of 10"5M and a rate of 3 Hz rhythm 1 Standard error of the mean 2 Not a compound of the invention, US 5,155,268 TABLE2 to. Maximum increase in the QTc interval (m sec) from the base line of the methoxamine infusion. b. Total cumulative dose (mg / kg) of the test compound when this value is measured. c. Maximum increase in the duration of the ventricular monophasic action potential (m sec), from the base line of the methoxamine infusion, measured at 90% repolarization. d. Magnitude of the maximum posterior depolarization amplitude maximum as a percent of the amplitude of monophasic action potential (APA). and. Ratio of the number of animals that developed polymorphic ventricular tachycardia to the total number of animals evaluated. F. Total accumulated dose in the first incidence of PVT. g. Racemic form of Example 1 for comparison, is not a compound of this invention. h. Racemic form of Example 2 for comparison, is not a compound of this invention. i. Racemic form of Example 3 for comparison, is not a compound of this invention. j. Compound for comparison, it is not a compound of this invention.

EXAMPLE 1 (E) -2-FRTMEDTIATEQ dj = ¡(S) - (-) -N- f4- [4- [et (7-fluoroheptyl) amino-1-hydroxybutyl] phenyl-ethanesulfonamide (2: 1 salt) Stage I . N-ethyl-gamma-oxo-4- (methanesulfonylamino) -benzene-butanamide A 'stirred suspension of 4- ((methanesulfonyl) amino) -gamma-oxobenzene-butanoic acid (described in EP 164 865) (20 g, 0.0737 moles) in THF (600 ml) it is treated with 13.7 ml (0.098 ml) of triethylamine and cooled to -12 ° C in an ice-methanol bath. This mixture is treated in drops with isobutyl chloroformate (12.7 ml, 0. 098 moles) and kept at -12 ° C for 1.5 hours. A solution of ethylane (4 g, 0.089 moles) and triethylamine (13.7 ml, 0.098 moles) in THF (173 ml) is then added in drops. The mixture is kept at -12 ° C for 3 hours and emptied into 780 ml of 1N HCl cooled with ice. Nitrogen is bubbled through this mixture to remove the THF. The solid is collected by washing by filtration with aqueous NaHCO3 and water and dried in vacuo to give 14.27 g of the product, without purification. The additional product (4 g) was obtained by extracting the acid filtrate with EtOAc. The combined product is washed with MeOH and dried to give 13.75 g of N-ethyl-gamma-oxo-4- ((methanesulfonyl) amino) benzene-butanamide. The analytical sample was recrystallized from acetonitrile and had a p.f. 210-213 ° C. Analysis calculated for i3Hi8N2 ° 4S: C '52.34; H, 6.08; N, 9.39; S, 10.75. Found: C, 52.02; H, 6.26; H, 9.28; S, 10.63.

Stage II. (S) - (-) - N-ethyl-gamma-hydroxy-4- (methanesulfonyl-amino) benzenebutanamide A stirred solution of the product of Step I (490.1 g, 1.64 moles) in THF (4 1), under nitrogen, is cooled from -30 to -35 ° C and treated for 1.5 hours with a solution of (-) - B-chlorodiisopinocampheylbovane (920 g), 2.86 moles) in THF (2 1). The mixture is stirred at -25 ° C for 3.5 hours when the reaction was complete by means of TLC with 10% MeOH-CH2Cl2 on silica gel. It is then treated with diethanolamine (600 ml) while heating at 0 ° C. This mixture is maintained at 0-10 ° C for 10 minutes and at room temperature (24 ° C) for 18 hours. The resulting mixture is concentrated to a suspension, while MeOH is added to displace the residual solvent. The concentrate is mixed with MeOH and washed with heptane. The MeOH solution is concentrated to an oil which is chromatographed on silica gel with MeOH mixtures and containing 0-10% MeOH. A solution of the resulting product in acetonitrile is mixed with tert-butyl ethyl ester and allowed to crystallize at 0 ° C to give the title product: m.p. 137-138 ° C; a] D24 -16 ° (c 0.95, EtOH); Analysis calculated for C ^^ Q ^ C ^ S: C '5198; H, 6.71; N, 933; S, 10.68. Found: C, 51.88; H, 6.82; N, 9.10; S, 10.53. The chiral purity of the title product is determined by first allowing a sample in acetonitrile to react with 1-naphthyl isocyanate and then analyzing the product derivatized by CLAP on a D-phenylglycine covalent column of Pirkle. It was a 99.5% pure (-) enantiomer.

Stage III. (S) - (-) - N- [4- [4- (ethylamino) -1-hydroxybutyl] -phenyl] methanesulfonamide A 65% solution of sodium bis (2-ethoxyethoxy) aluminum hydride in toluene (44 ml, 0.146 moles) is mixed with THF (100 ml) under nitrogen and the stirred mixture is treated, in portions over 2 hours, with a suspension of the product of Step II (11.45 g, 0.0381 moles) in THF (360 ml). An exothermic reaction increases the temperature of the reaction mixture at 34 ° C during this addition. The mixture is kept at room temperature (24 ° C) for 18 hours, cooled to 8 ° C and treated, in drops for 10 minutes, with 6M H2SO4 (3 ml). The cooled bath is removed and the mixture is treated with 6M H2SO4 (19 ml) for 2 hours; the pH of the mixture was 10. This mixture is treated with MeOH (150 * ml) and stirred for 2.5 hours. The solid is collected by filtration and washed with 10% MeOH-CH 2 Cl 2 (800 ml). The combined filtrate is concentrated and the residue is recrystallized from EtOH to give 5.8 g of the title product: m.p. 168-170 ° C; [α] D -20 ° (C 0.85, MeOH); Analysis Calculated for Cj ^ I ^^ C ^ S; C, 54.51; H, 7.74; N, 9.78; S, 11.20. Found: C, 54.32; H, 7.52; N, 9.96; S, 11.05.

Stage IV. l-Bromo-7-fluoroheptane A stirred solution of 7-bromo-1-heptanol (1.53 g, 7.85 mmol) in 2.5 ml of CC14 is cooled in a bath with ice under nitrogen, and treated with 2.25 ml (17.0 mmol) from DAST; The flask is covered with a Teflon cap and secured with a plastic lock. The mixture is stirred in cold for 30 minutes and then the ice bath is removed at room temperature. After 4.5 hours an aliquot is tested by TLC to show the unreacted starting material; 0.7 ml (5.3 mmol) of the DAST was added, the flask was capped and stirred at room temperature overnight. The resulting mixture is added dropwise to 25 ml of ice / water for 5 minutes and this is extracted with hexane. The organic extracts are washed sequentially with water, 10% aqueous Na 2 CO 3 and brine. The extract meets, dries (MgSO4) and concentrate. The residue is chromatographed under pressure on 300 ml of silica gel, mesh (230-400) with 4% CH2Cl2hexane to give 0.9 g (53%) of the product, 1-bromo-7-fluoroheptane: NMR (CDC13) d 1.43 (m, 6H) < 1.71 (m, 2H), 1.87 (m, 2H), 3.42 (t, 2H), 4.37, 4.52 (broad t, 2H).

Step V. (E) -2-Butenedioate of (S) - (-) - N - [4- [4- [Ethyl (7-fluoroheptyl) amino] -1-hydroxybutyl] phenyl] -methanesulfonamide (2: 1 salt) ) A stirred mixture of the product of Step III (2.58 g, 0.009 mole), the product of Step IV (2.0 g, 0.01 mole), NaHCO3 powder (1.68 g, 0.02 mole) and acetonitrile (80 ml) is carried reflux under nitrogen for 18 hours and then concentrate in vacuo. A mixture of the residue and the water is extracted with EtOAc. The extract is washed with water and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel with 6% MeOH -0.3% H 4 OH-CHCl. A solution of the product thus obtained in EtOAc is washed with water and brine, dried (MgSO 4) and concentrated to give 1.92 g (0.00476 moles) of (S) - (-) - N- [4- [4- [Ethyl. (7-fluoroheptyl) amino] -1-hydroxybutyl] phenyl] -methanesulfonamide. A solution of this material in acetone is mixed with 0.276 g (0.00238 moles) of fumaric acid and the resulting salt is crystallized from acetone to give 1.78 g of the title product: m.p. 126-127 ° C; [] D -15 ° (c 1.0, EtOH); Analysis Calculated for C ^^ - yF ^ OgS; C, 57.36; H, 8.10; Nj 6. 08; S, 9.96. Found: C, 57.30; H, 8.08; N, 5.94; S, 6.94.

Example 2 (E) -2-Bytendicate of (S) - (r) -N- f4-f4-phenyl (6-fluoroheptyl) amino] -1-hydroxybutyl phenyl-methanesulfonamide (2: 1 salt) Step I. Acid 6 -hydroxyheptanoic,? -lactone A solution of 2-methylcyclohexanone (11.1 g, 0.099 moles) in chloroform (15 ml) is added during 20 minutes, under nitrogen, to a stirred suspension of m-chloroperbenzoic acid (24.6 g, 0.143 moles). ) in chloroform (250 ml). After 3 hours, 40 minutes, the mixture is poured into aqueous sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine (MgSO4) and concentrated. The residue is distilled from a small amount of K2CO3 to give 9.58 g, e.g. 78-79 ° C (2.5-3 mm Hg) of 6-hydroxyheptanoic acid, e-lactone.

Stage II. Ethyl 6-hydroxyheptanoate A solution of 6-methyl-e-caprolactone, the product of Step I (18.94 g, 0.148 mol) in 65 ml of absolute EtOH is treated with 0.8 ml of concentrated H2SO4, stirred at room temperature for 7 hours and concentrate in vacuo. The residue is treated with ice and neutralized with dilute NaHCO 3. The aqueous mixture is extracted with Et20 and the extracts are washed with water and then with brine. The extract is combined, dried (MgSO4) and concentrated to give 24.38 g of the crude product. This is combined with the product from a previous reaction and distilled to give 18.45 g, e.g. 96 ° C (2.2 mm Hg) and 6.73 g, e.g. 91 ° C (0.8 mm Hg) of the title product.

Stage III. Ethyl 6-fluoroheptanoate A solution of the product from Step II (18.4 g, 0.106 moles) in 200 ml of CH2C12, under nitrogen, is cooled to -72 ° C in a dry ice-acetone bath and treated in drops with a solution of 30 ml (0.225 moles) of Et2NSF3 (DAST) in CH2C12 (195 ml) for 1 hour. The mixture is stirred at -72 ° C for 1 hour and then for 2 hours while the mixture is allowed to warm to 5 ° C (by periodic addition of acetone to the bath). The mixture was kept at 5 ° C for 15 minutes then, it was poured into a mixture of 600 ml of 10% Na 2 CO 3 and 200 ml of ice with vigorous stirring (foaming). The pH of the resulting aqueous mixture was 7. This is extracted with Et20; the extracts are washed with water and brine, dried (MgSO4) and concentrate. The residue is distilled to give 7.16 g (38.5%) of the title product, e.g. 76-78 ° C (5.8 mm Hg): NMR (CDC13) d 1'.26 (m, 4.5H), 1.35 (d, 1.5H), 1.57 (m, 6H), 2.32 (t, 2H), 4.13 (c, 2H), 4.57, 4.72 (broad m, 1H).

Stage IV. 6-Fluoro-l-heptanol To a mixture of 3.64 g (0.096 mole) of .LiAlH4 in 200 ml of Et20, under N2, at 4 ° C a solution of the product from Step III (10.4 g, 0.059 mole) is added. in 35 ml of Et20 for 45 minutes. The mixture is stirred cold for 15 minutes and allowed to warm to room temperature for 100 minutes. The mixture is cooled in an ice bath and treated in drops for 40 minutes with 35 ml of saturated aqueous Na2SO4; 200 ml more of Et20 are added and after stirring at room temperature for 15 minutes the mixture is filtered through a pad of Na2SO4. The filter cake is washed well with Et20 and the filtrate concentrated in vacuo. The residue is distilled to give 4.8 g (60.7%) of the title product, e.g. 85-87 ° C (9.2 mm Hg), which by means of NMR is slightly contaminated by an alkene, and 0.58 g (7.3%) of the clean product; e.g. 85-87 ° C (9.2 mm Hg); NMR (CDCl3) d 1.27, 1.35 (broad d, 3H), 1.55 (m, 9H), 3.65 (t, 2H), 4.58, 4.73 (broad m, 1H).

Step V. l-Bromo-6-fluoroheptane A solution of triphenylphosphine (10.32 g, 0.0393 mol) and the product of Stage IV (4.8 g, 0.0358 mol) in 75 ml of benzene, under nitrogen, is cooled in a bath of ice and treated, in portions for 40 minutes with 7.0 g (0.0393 moles) of N-bromosuccinimide. The mixture is stirred in the cold for 20 minutes and at room temperature for 2.5 hours. This mixture is poured into 250 ml of pentane, a precipitate is removed by filtration and the filtrate is concentrated at room temperature in vacuo. The solid is treated with 300 ml of pentane, the mixture is cooled, a solid is removed by filtration and the filtrate is concentrated to 100 ml.

This is cooled and a solid is removed by filtration. The filtrate is concentrated at room temperature in vacuo. The residue is treated with 200 ml of Et20 and the solution is washed with Na2S203 5%, NaOH 0.5N and then brine, dried (MgSO4) and concentrated in vacuo at room temperature to give 6.6 g (93.6%) of the title product: NMR (CDC13) d 1.22, 1.28 (broad d, 3H), 1.57 (m, 6H), 1.88 (m, 2H), 3.42 (t, 2H), 4.57, 4. 73 (broad, 1H).

Stage VI. (E) -2-Butenedioate of (S) - (-) - N - [4- [4- [Ethyl (6-fluoroheptyl) amino] -1-hydroxybutyl] phenyl] -methanesulfonamide (salt 2: 1) A mixture agitated of the product of Example 1Stage III (2.58 g, 0.009 mole), the product from Step V (2.0 g, 0.01 mole), NaHCO3 powder (1.68 g, 0.02 mole) and acetonitrile (80 ml) was brought to reflux under nitrogen for 18 hours and concentrates in vacuo. The residue is mixed with water and extracted with EtOAc. The extract is washed with water and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel with 6% MeOH-0.3% NH4OH-CHCl3. A solution of the resulting product in EtOAc is washed with saturated NaHCO 3, water and brine, dried (MgSO 4) and concentrated to give 1.79 g (0.00443 mol) of (S) - (-) - N- [4- [4- [ethyl (6-fluoroheptyl) amino] -1-hydroxy-butyl] phenyl] -methanesulfonamide. A solution of this material in acetone is mixed with 0.257 g (0.00222 mol) of fumaric acid and the salt is crystallized from acetone to give 1.26 g of the title product: m.p. 108-111 ° C; [α] D -14 ° (c 1.0, EtOH); Analysis Calculated for C22H37FN205S: C, 57.36; H, 8.10; N, 6.08; S, 6.96. Found: C, 57.27; H, 8.08; N, 6.02; S, 6.90.

Example 3_ (S) - (-) - N- [4- [4- phenyl (6-fluoro-6-methylheptyl) -amino] -1-hydroxybutyl] phenyl-methanesulfonamide Stage I. 5-Chloropentyl-2-tetrahydropyranyl ether A solution of pentamethylene chlorohydrin (10.0 g, 0.0816 mole) in Et20 (165 ml) under nitrogen is treated with 3,4-dihydro-2H-pyran (10.3 g, 0.122 mole) and hydrate. p-Toluenesulfonic acid (0.5 g) and kept at room temperature for 4.5 hours. The mixture is washed with aqueous NaHCO 3 and brine, dried (MgSO 4) and concentrated. The residue is distilled to give 4.06 g, e.g. 79-82 ° C (0.1-0.07 mm Hg) and 10.54 g, e.g. 82-84 ° C (0.1- 0.07 mm Hg) of 5-chloropentyl-2-tetrahydropyranyl ether.

Stage II. 6-Hydroxy-6-methylheptyl-2-tetrahydropyranyl ether A small portion of a solution of the product from Step I (21.1 g, 0.102 mol) in THF (105 ml) is added, under nitrogen, to magnesium chips (5.0 g, 0.204 g-atom). The mixture is heated in an oil bath at 75-80 ° C and the reaction is initiated by the addition of 1.5 ml of a solution of 1,2 M-1,2-dibromoethane in THF. The remaining chloroalkane solution is then added for 20 minutes. The resulting mixture is refluxed for 45 minutes, cooled in an ice bath and treated for 15 minutes with a solution of acetone (9.0 ml, 0.123 ml) in THF (95 ml). It is kept at room temperature for 1 h, cooled in an ice bath and treated for 15 minutes with aqueous, saturated NH 4 Cl (115 ml). The resulting mixture is extracted with EtO. The extract is washed with water and brine, dried (MgSO 4) and concentrated to give 30.5 g of the product without purification. Distillation gives 16.77 g of 6-hydroxy-6-methylheptyl-2-tetrahydropyranyl ether, e.g. 107-115 ° (0.07-0.1 mm Hg). The mass spectrum Cl had m / z 231 (M + H) +.

Stage III. 6-Fluoro-6-methylheptyl-2-tetrahydropyranyl ether A solution of the product from Step II, (3.97 g, 0.0173 mol) in CH 2 Cl 2 (12 mL) is added under nitrogen, for 4.5 minutes to a stirring solution of diethylaminosulfide trifluoride. (4.6 ml, 0.0345 moles) in CH2C12 (12 ml) which had been cooled in an acetone bath of dry ice (~78 ° C). The mixture is kept in the bath for 15 minutes, heated at 0 ° C for 10 minutes and mixed with 10% aqueous Na 2 CO 3 (60 ml). This mixture is extracted with CH2C12. The extracts are washed with water, dried (MgSO 4) and concentrated. The residue is chromatographed on silica gel with 0.05% Et3N-2.5% EtOAc-hexane to give 3.36 g of 6-fluoro-6-methylheptyl-2-tetrahydropyranyl ether.

Stage IV. 6-Fluoro-6-methyl-I-heptanol A stirring solution of the product of the Stage III (3.34 g, 0.0144 mol) in absolute EtOH is treated with pyridinium p-toluenesulfonate (0.47 g, 0.00187 mol) and kept under nitrogen at room temperature for 41 hours. The mixture is concentrated and the residue is dissolved in EtOAc, washed with aqueous NaHC03? Brine, dry (MgSO4) and concentrate. The residue is chromatographed on silica gel with 5 to 20% EtOAc-hexane to give 1.86 g of 6-fluoro-6-methyl-1-heptanol.

Step V. 1-Bromo-6-fluoro-6-methylheptane A stirring solution of the product from the Stage IV (0.427 g, 0.00288 mol) in benzene (5.2 ml) is mixed with triphenylphosphine (0.83 g, 0.00317 mol), cooled in an ice bath and treated in portions for 26 minutes with N-bromosuccinimide (0.56 g, 0.00317 moles). ). The mixture is kept in the ice bath for 30 minutes and at room temperature for 3.5 hours; It is then diluted with pentane (20 ml), cooled in an ice bath for -3 minutes and filtered. The solid is washed with pentane and the filtrate is concentrated. A mixture of the residue and pentane is cooled in an ice bath for a few minutes and again filtered. The filtrate is mixed with Et20 and washed successively with cold 5% aqueous sodium thiosulfate, 0.5 N NaOH and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel with 1-3% EtOAc-hexane to give 0.440 g of l-bromo-6-fluoro-6-methylheptane.

Stage VI. (S) - (-) - N- [4- [4- [Ethyl (6-fluoro-6-methylheptyl) -amino] -1-hydroxybutyl-J-phenyl] -methanesulfonamide A stirring mixture of the product of Example 1, Stage III (2.0 g, 0.00698 moles), the product of Stage V (1.62 g, 0.00768 moles), sodium bicarbonate (1.17 g, 0. 0140 moles) and acetonitrile (60 ml) is brought to reflux, under nitrogen for 16 hours, cooled and filtered. The filtrate is concentrated in vacuo and the residue is chromatographed on silica gel with 5% MeOH-0.5% NH4OH-CH2Cl2 to give an oil 2.42 g of the title product. The mass spectrum High resolution FAB had (M + H) + at m / z 417. Theory for C21H38FN203S: 417.2587; measured: 417.2602.

Claims (6)

1. An enantiomeric compound (S) of Formula I or their pharmacologically acceptable salts, characterized in that: R3 is C1-9alkyl substituted with a fluorine atom.

2. The compound according to claim 1, characterized in that R3 is Cg_g alkyl substituted with a fluorine atom.

3. The compound according to claim 1, characterized in that it is: a) (E) -2-Butenedioate of (S) - (-) - N- [4- [4- [Ethyl (7-fluoroheptyl) amino] -1 -hydroxybutyl] phenyl] -methanesulfonamide (salt 2: 1); b) (E) -2-Butenedioate of (S) - (-) - N- [4- [4- [Ethyl (6-fluoroheptyl) amino] -1-hydroxybutyl] phenyl] -methanesulfonamide (Ps 2: 1); or c) (S) - (-) - N- [4- [4- [Ethyl (6-fluoro-6-methylheptyl) -amino] -1-hydroxybutyl] phenyl] -methanesulfonamide.

4. A use of a compound of Formula I or its pharmaceutically acceptable salts in the preparation of a medicament useful in the treatment of cardiac arrhythmia in patients, by administering a therapeutically effective amount.

5. The use according to claim 4, wherein the effective amount is from about 0.01 to about 300 mg.

6. The use according to claim 4, wherein the compound is in a unit dosage form for oral, sublingual, transdermal or parenteral administration.