EP1606237A1

EP1606237A1 - 2-(butyl-1-sulfonylamino)-n- 1(r)-(6-methoxy-pyridin-3-yl)-propyl]-benzamid, the use thereof in the form of drug an pharmaceutical preparations containing said compound

Info

Publication number: EP1606237A1
Application number: EP04717628A
Authority: EP
Inventors: Joachim Brendel; Heinz Goegelein; Klaus Wirth; Gert Ulrich Kuerzel
Original assignee: Sanofi Aventis Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2003-03-18
Filing date: 2004-03-05
Publication date: 2005-12-21
Also published as: MY176510A; CA2519022A1; WO2004083157A1; HK1086819A1; CN100361943C; JP2006520343A; PE20050307A1; BRPI0408441A; MXPA05009763A; DE10312073A1; AR043622A1; TW200500342A; NZ542476A; MA27749A1; CN1756728A; RU2005132163A; HRP20050815A2; ZA200506328B; AU2004222137A1; NO20054472L

Abstract

The invention relates to 2-(Butyl-1-sulfonylamino)-N-[1 (R)-(6-methoxy-pyridin-3-yl)-propyl]-benzamid of formula (I), and to the pharmaceutically acceptable salts thereof. Said invention also relates to the production and use of the inventive compound or the pharmaceutically acceptable salts thereof, in particular for treating and preventing auricular arrhythmia, for example auricular fibrillation (atrial fibrillation) or auricular flutter (atrial flutter).

Description

description

2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide, its use as a medicament and pharmaceutical compositions containing the same

The invention relates to the 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) - propyfj-benzamide of the formula I, as well as its pharmaceutically acceptable salts, their preparation and Use, especially in medicines.

The compound of formula I and its pharmaceutically acceptable salts can reduce the incidence of atrial arrhythmias without effect on the ventricle or other side effects. The compound of the invention and its pharmaceutically acceptable salts are therefore particularly suitable as a novel antiarrhythmic agent, in particular for the treatment and prophylaxis of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter (atrial flutter).

Atrial fibrillation and atrial flutter are the most common, persistent ones

Cardiac arrhythmias. The incidence increases with age and often leads to fatal consequences, such as brain stroke. AF affects approximately 1 million Americans annually and causes more than 80,000 strokes every year in the US. The currently used Class I and Class III antiarrhythmic agents reduce the recurrence rate of AF, but because of their potential proarrhythmic Side effects only limited use. Therefore, there is a great medical need for the development of better drugs for the treatment of atrial arrhythmias (S.Nattel, Am., Heart J. 130, 1995, 1094-1106, "Newer developments in the management of atrial fibrillation").

It has been shown that most supraventricular arrhythmias are subject to so-called "reentry" excitation waves, such reentries occur when cardiac tissue has slow conduction and very short refractory periods Increasing the myocardial refractory period by prolonging the action potential is a recognized mechanism To stop arrhythmias or to prevent them from arising (TJ Colatsky et al, Drug Dev. Res. 19, 1990, 129-140; "Potassium Channels as Targets for Antiarrhythmic Drug Action"). The length of the action potential is essentially determined by the extent of repolarizing

K ⁺ currents, which flow out of the cell via different K ⁺ channels. Of particular importance is attributed to the so-called "delayed rectifier" IK, which consists of 3 different components: IK _r , IK _S and IK _ur .

Most known class III antiarrhythmics (for example, dofetilide, E4031, and d-sotalol) predominantly or exclusively block the rapidly activating potassium channel IK _r found in both human and ventricular cells

Proving proving ground. However, it has been found that these compounds have an increased proarrhythmic risk at low or normal heart rates, in particular arrhythmias which are referred to as "torsades de pointes" (DM Roden, Am. J. Cardiol., 72, 1993). 44B - 49B: "Current Status of Class III Antiarrhythmic Drug Therapy.") In addition to this high, sometimes fatal, low-frequency risk, lK _r blockers experienced a decrease in efficacy in conditions of tachycardia in which the effect was needed is determined ("negative use-dependence").

The "very fast" activating and very slowly inactivating component of the delayed rectifier IK _ur (= ultra-rapidly activating delayed rectifier), which is the Kv1.5-

Kanai corresponds, plays a particularly large role for the repolarization in the human forecourt. An inhibition of IK _ur potassium outward current is thus in

Compared to the inhibition of IK _r or IK _S a particularly effective method for

Prolongation of the atrial action potential and thus the termination or prevention of atrial arrhythmias.

In contrast to IK _r and IK _S , which also occur in the human ventricle, the IK _ur plays an important role in the human atrium, but not in the

Ventricle. For this reason, when inhibiting the IK _ur current in contrast to

Blockade of IK _r or IK _S precludes the risk of a proarrhythmic effect on the ventricle. (Z. Wang et al., Circ.Res 73, 1993, 1061-1076: "Sustained Depolarization-Induced Outward Current in Human Atrial Myocytes"; G.-R. Li et al, Circ.Res. 78, 1996, 689 - 696: "Evidence for Two

Components of Delayed Rectifier K ⁺ -Current in Human Ventricular Myocytes "; GJ Arnos et al., J. Physiol. 491, 1996, 31-50:" Differences between outward currents of human atrial and subepicardial ventricular myocytes ").

However, antiarrhythmics that act via selective blockade of the IK _ur current or Kv1.5 channel are not yet available on the market.

The enantiomer 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide claimed in this application has not previously been described. The corresponding racemate is mentioned in the patent application WO 0288073 as an example. The compound of the formula I is distinguished by surprising advantages.

It has now surprisingly been found that the antiarrhythmic effect in a model on the anesthetized pig for the novel 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl ] benzamide of the formula I while the corresponding 1 (S) -enantiomer is less effective. Furthermore, it has been found that the compound of formula I has no effect on the QTc interval and no negative inotropic or hemodynamic side effects. The experiments prove that compound I can be used as a novel antiarrhythmic drug with a particularly advantageous safety profile. In particular, the compound is useful in the treatment of supraventricular arrhythmias, for example, atrial fibrillation or atrial flutter. The compound can be used to terminate existing atrial fibrillation or flutter to regain the sinus rhythm (cardioversion). In addition, it reduces the susceptibility to the emergence of new flicker events (preservation of the sinus rhythm, prophylaxis).

The present invention relates to 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide of the formula I, as well as its pharmaceutically acceptable salts.

Since the compound I contains a basic pyridine radical, it can also be used in the form of its pharmaceutically acceptable acid addition salts with inorganic or organic acids, for example as hydrochloride, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate, etc. Die Existing sulfonamide moiety also allows the formation of alkali or alkaline earth metal salts, preferably the sodium or potassium salt, or ammonium salts, for example salts with organic amines or amino acids. The pharmaceutically acceptable salts can be obtained from the compound of the formula I by customary processes, for example by combining with an acid or base in a solvent or dispersant or else by anion or cation exchange from other salts.

Preferably, the free compound is 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide of the formula I.

The compound of the formula I can be prepared by different chemical processes, two of which are illustrated in Scheme 1. The coupling of the sulfonylaminobenzoic acid of formula II with the amine of formula III can either directly from the acid in the presence of a conventional coupling reagent take place, or for example from an activated acid derivative such as the acid chloride. When using racemic 1- (6-methoxypyridin-3-yl) -propylamine of the formula III, the cleavage into the enantiomers takes place on the final stage, for example by chiral chromatography or classical resolution. Alternatively, by using 1 (R) - (6-methoxy-pyridin-3-yl) -propylamine of formula IIIa directly the desired enantiomer can be obtained. The preparation of the sulfonylaminobenzoic acid of the formula II is carried out in a manner known to those skilled in the art from the commercially available substances aminobenzoic acid and butylsulfonyl chloride.

Scheme 1:

The subject of this application likewise includes the compound 1- (6-methoxypyridin-3-yl) -propylamine of the formula III used as an intermediate, and also the enantiomers thereof, in particular the 1 (R) - (6-methoxypyridine-3-yl) yl) -propylamine of the formula IIIa, and their use for the preparation of active pharmaceutical ingredients, for example 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl ] - benzamide. 1- (6-methoxypyridin-3-yl) propylamine of the formula III can be prepared by different chemical processes from commercially available compounds, two of which are shown as examples in Scheme 2. First, 5-bromo-2-methoxypyridine can be first metallated with butyllithium, then reacted with propionitrile and then reduced with sodium borohydride to the compound of formula III. Alternatively, 3-cyano-6-methoxypyridine can be reacted with ethylmagnesium bromide and then reduced with sodium borohydride. The cleavage into the enantiomers can be carried out by customary methods, for example chromatography on a chiral phase, classical resolution by means of a chiral acid or by enzymatic methods.

Scheme 2:

1.) Ethylmagnesium bromide 2.) Sodium borohydride III

The compound of the formula I according to the invention and its physiologically tolerable salts can be used on animals, preferably on mammals, and in particular on humans, as medicaments on their own or in the form of pharmaceutical preparations. The present invention is also the compound of formula I and their physiologically acceptable salts for use as medicaments, their use in the therapy and prophylaxis of

Cardiac arrhythmias, supraventricular arrhythmias, atrial fibrillation and / or atrial flutter and their use in the manufacture of medicines for this. Furthermore, the present invention relates to pharmaceutical preparations containing as active ingredient an effective dose of the compound of formula 1 and / or a physiologically acceptable salt thereof in addition to conventional, pharmaceutically acceptable carriers and excipients. The pharmaceutical preparations normally contain from 0.1 to 90% by weight of the compound of the formula I and / or its physiologically tolerable salts. The preparation of the pharmaceutical preparations can be carried out in a manner known to the person skilled in the art. For this purpose, the compound of the formula I and / or its physiologically tolerable salts is brought together with one or more solid or liquid galenic excipients and / or excipients and, if desired, in combination with other active pharmaceutical ingredients in a suitable dosage form or dosage form, which then as Medicaments can be used in human medicine or veterinary medicine.

Medicaments containing the compound of the formula I according to the invention and / or its physiologically tolerated salts may be administered, for example, orally, parenterally, e.g. B are administered intravenously, rectally, by inhalation or topically, the preferred application depending on the individual case, for example the particular appearance of the disease to be treated.

Which excipients are suitable for the desired drug formulation is familiar to the person skilled in the art on the basis of his specialist knowledge. In addition to solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers, means for achieving a depot effect, buffer substances or dyes.

The compound of the formula I can also be combined with other active pharmaceutical ingredients to obtain an advantageous therapeutic effect. Thus, advantageous combinations with cardiovascular active substances are possible in the treatment of cardiovascular diseases. As such, for cardiovascular diseases advantageous combination partners come, for example, other antiarrhythmic drugs, so Class I, Class II or Class III antiarrhythmic agents in question, such as IK _S or IK _r channel blockers, for example dofetilide, or further hypotensive substances such as ACE inhibitors (for example enalapril, captopril, ramipril), angiotensin

Antagonists and K ⁺ channel activators, as well as alpha-receptor blockers, but also sympathomimetic and adrenergic compounds, as well as Na ⁺ / H ⁺ -

Exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotropic substances, such as digitalis glycosides, or

Diuretics.

For an oral application form, the active compound with the appropriate additives, such as carriers, stabilizers or inert diluents, mixed and brought by the usual methods in the appropriate dosage forms, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch may be used. The preparation can be carried out both as a dry and as a wet granules. Suitable oily carriers or as solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof. Further auxiliaries, also for other forms of application, are, for example, polyethylene glycols and polypropylene glycols.

For subcutaneous, intramuscular or intravenous administration, the active compound, if desired with the customary substances such as solubilizers, emulsifiers or other excipients, in solution, suspension or emulsion. The compound of formula I and its physiologically acceptable salts may also be lyophilized and the lyophilizates obtained used, for example, for the preparation of injection or infusion preparations. Suitable solvents include, for example, water, physiological saline solution or alcohols, for example ethanol, propanol, glycerol, in addition to sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active ingredient of the formula I or its physiologically acceptable salts in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents. The formulation may also contain, as needed, other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation usually contains the active ingredient in a concentration of about 0.1 to 10, in particular from about 0.3 to 3 weight percent. The dosage of the active ingredient of the formula I to be administered or of the physiologically tolerable salts thereof depends on the individual case and, as usual, must be adapted to the conditions of the individual case for optimum action. Of course, it depends on the frequency of administration but also on the type and strength of the disease to be treated and on gender, age, weight and individual responsiveness of the person or animal to be treated and whether it is acute or chronic treatment or prophylaxis. The daily dose of a compound of formula I when administered to a patient weighing about 75 kg is usually 0.01 mg / kg body weight to 100 mg / kg body weight, preferably 0.1 mg / kg body weight to 20 mg / kg body weight. The dose may be administered in the form of a single dose or divided into several, for example two, three or four, single doses. Especially in the treatment of acute cases of cardiac arrhythmias, for example in an intensive care unit, parenteral administration by injection or infusion, for example by continuous intravenous infusion, may also be advantageous.

Experimental part

Preparation of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxy-pyridin-3-yl) -propyl] -benzamide

a) 2- (Butyl-1-sulfonylamino) benzoic acid To a suspension of 20 g (146 mmol) of 2-aminobenzoic acid in 250 ml of water was added 20 g (188 mmol) of sodium carbonate. Subsequently, 11.4 g (72.8 mmol) of butylsulfonyl chloride were added dropwise and the reaction mixture was stirred for 2 days at room temperature. It was acidified with concentrated hydrochloric acid, stirred for 3 hours at room temperature and the precipitated product was filtered off with suction. After drying in vacuo, 9.6 g of 2- (butyl-1-sulfonylamino) benzoic acid were obtained.

b) 1- (6-methoxy-pyridin-3-yl) -propylamine

Method 1

To a solution of 10.2 ml of n-butyllithium (2.5 M solution in hexane, 25.5 mmol) in 50 ml of diethyl ether at -70 ° C was added 3 ml (23.2 mmol) of 5-bromo-2-methoxypyridine added. After 10 minutes, 1.4 ml (19.5 mmol) of propionitrile were added. After 2 hours at -70 ° C, the reaction mixture was allowed to slowly rise to room temperature. Then, 2.2 g of sodium sulfate decahydrate was added and allowed to stir for 1 hour. After subsequent addition of 5 g of magnesium sulfate, the salts were filtered off after brief stirring and the filtrate was concentrated. The residue was dissolved in 70 ml of methanol, and at 0 ° C., 1.1 g (28 mmol) of sodium borohydride was added. After stirring overnight, the reaction mixture was adjusted to pH 2 with concentrated hydrochloric acid and concentrated on a rotary evaporator. The residue was mixed with 10 ml of water and extracted once with diethyl ether. Subsequently, the aqueous phase was saturated with sodium bicarbonate, concentrated in vacuo and the residue extracted with ethyl acetate. After drying and concentration of the ethyl acetate extracts, 1.4 g of racemic 1- (6-methoxypyridin-3-yl) -propylamine were obtained.

The enantiomers were separated by preparative HPLC on a Chiralpak ADH column (250x4.6 mm); Eluent: heptane / ethanol / methanol 50: 1: 1 with 0.1% diethylamine; Temperature: 30 ° C; Flow rate 1 ml / min. First, at a retention time of 18.4 minutes, 0.45 g of 1 (S) - (6-methoxypyridin-3-yl) -propylamine was eluted. Subsequently, 0.42 g of 1 (R) - (6-methoxypyridin-3-yl) -propylamine were obtained at a retention time of 21, 0 min.

Method 2

To a solution of 20 g (150 mmol) of 6-methoxynicotinonitrile and 0.62 g (3.3 mmol) of copper (I) iodide in 125 ml of anhydrous tetrahydrofuran was added at 0 ° C under argon 170 ml (170 mmol) of a 1 M solution of ethyl magnesium bromide in tetrahydrofuran was added dropwise in 30 minutes. After 30 minutes, the reaction mixture was allowed to come to room temperature and stirred for a further 3 h. 200 ml of methanol were then added dropwise at 5 ° -10 ° C. and then 11.3 g (299 mmol) of sodium borohydride were added in portions. After stirring overnight at room temperature, 300 ml of water were added and extracted 3 times with 250 ml of ethyl acetate each time. The organic phase was dried over magnesium sulfate, then concentrated and the residue purified by chromatography. 5.5 g of racemic 1- (6-methoxy-pyridin-3-yl) -propylamine were obtained.

c) 2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide and 2- (Butyl-1-sulfonylamino) -N- [ 1 (S) - (6-methoxy-pyridin-3-yl) -propyl] -benzamide

Method 1

To a solution of 8.0 g (31.1 mmol) of 2- (butyl-1-sulfonylamino) benzoic acid in 250 ml of tetrahydrofuran was added 4.4 g (32.7 mmol) of 1-hydroxy-1H-benzotriazole and 6 , 3 g (32.7 mmol) of N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride was added and the reaction mixture was stirred for 90 minutes. Then, a solution of 5.4 g (32.7 ^'mmol) of racemic 1- (6-methoxy-pyridin-3-yl) -propylamine was added dropwise in 20 ml of tetrahydrofuran and stirred overnight. The reaction mixture was treated with 250 ml of water and extracted with 300 ml of ethyl acetate. The organic phase was extracted 5 times with 100 ml of saturated sodium bicarbonate solution and then dried over magnesium sulfate. This gave 9.0 g of 2- (butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) propyl] benzamide. The enantiomers were separated by preparative HPLC on a Chiralpak ADH column (250x4.6 mm); Eluent: heptane / ethanol / methanol 10: 1: 1; Temperature: 30 ° C; Flow rate: 1ml / min.

First, 4.0 g of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide was eluted at a retention time of 5.9 min , After a mixed fraction, 3.0 g of 2- (butyl-1-sulfonylamino) -N- [1 (S) - (6-methoxypyridin-3-yl) -propyl] -benzamide were obtained at a retention time of 7.2 min receive.

Method 2 From 0.41 g (2.46 mmol) of 1 (R) - (6-methoxy-ρyridin-3-yl) -propylamine and 0.64 g (2.47 mmol) of 2- (butyl-1-sulfonylamino ) benzoic acid were prepared by coupling in the presence of 1-hydroxy-1H-benzotriazole and N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride analogous to Method 1 0.9 g of 2- (butyl-1-sulfonylamino) - N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide.

d) 2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxy-pyridin-3-yl) -propyl] -benzamide

2 g of the obtained according to Method 1 or Method 2 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) propyl] benzamide were dissolved in 9 ml of isopropanol in the heat was dissolved, then 8 ml of warm water was added and the reaction mixture allowed to cool slowly overnight. After filtration with suction at 0 ° C., 1.5 g of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide were obtained as colorless needle-shaped crystals ; Melting point 97 ° C. From suitable monocrystals, the absolute configuration was confirmed by X-ray diffraction analysis.

Pharmacological investigations

Human Kv1.5 channels were expressed in Xenopus oocytes. For this purpose, oocytes from Xenopus laevis were first isolated and defolliculated. Subsequently, in these oocytes in vitro synthesized Kv1.5 coding RNA was injected. After 1-7 days of Kv1.5 protein expression, Kv1.5 currents were measured on the oocytes using the two-microelectrode voltage-clamp technique. The Kv1.5 channels These were usually activated with 500 ms lasting voltage jumps to 0 mV and 40 mV. The bath was rinsed with a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl 2 1, 8 mM, MgCl 2 1 mM,

HEPES 5mM (titrated with NaOH to pH 7.4). These experiments were carried out at room temperature. For data collection and analysis, Geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D / A converters and software (AD Instruments, Castle Hill, Australia) were used. The substances according to the invention were tested by adding them to the bath solution in different concentrations. The effects of the substances were calculated as percent inhibition of the Kv1.5 control current obtained when no substance was added to the solution. The data were then extrapolated with the Hill equation to determine the inhibitory concentrations IC50 for the respective substances.

In this way, the following IC 50 values were determined for the compounds listed below:

2- (Butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) -propyl] -benzamide: IC50 = 2.4 μM

2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide of the formula I:

IC50 = 10 μM

2- (Butyl-1-sulfonylamino) -N- [1 (S) - (6-methoxypyridin-3-yl) -propyl] -benzamide: IC50 = 2.4 μM

Investigation of refractory period and left atrial vulnerability in pigs

The two enantiomers 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) propyl] benzamide of the formula I and 2- (butyl-1-sulfonylamino) - N- [1 (S) - (6-methoxypyridin-3-yl) -propyl] -benzamide was tested and compared to the anesthetic of the anesthetized pig for prolongation of the refractory period and antiarrhythmic activity. The refractory period of the left atrium was determined and the antiarrhythmic activity recorded as described in the literature (Knobloch et al. 2002. Naunyn-Schmiedeberg's Arch. Pharmacol. 366; 482-487). The antiarrhythmic effect refers to the inhibition of the occurrence of episodes of arrhythmias, which are triggered by a premature extrastimulus (S2) in the left atrium (= left atrial vulnerability).

In Table 1, a comparison of the effect of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide of the formula I and 2- ( Butyl-1-sulfonylamino) -N- [1 (S) - (6-methoxypyridin-3-yl) -propyl] -benzamide on the left atrial refractory period and antiarrhythmic potency in the anesthetized pig after a bolus dose of 3 mg / kg shown. The refractory period values are given as a percentage of the basal values 10 minutes after injection. Refractory mean values are shown in three frequencies (150, 200 and 250 / min). From the results summarized in Table 1 it can be seen that the R-enantiomer causes a much greater extension of the refractory period than the S-Ehantiomer. The triggered arrhythmias could be prevented by the R-enantiomer to 73.9%, while using the S-enantiomer, the occurrence of arrhythmias was inhibited only 27%.

Table 1 :

By repeated measurement after substance administration, the duration of action of a substance on the refractory period can also be determined in this test arrangement. The R-enantiomer was infused intravenously at a dose of 1 mg / kg for 100 minutes and the pharmacological activity was determined over 280 minutes. As shown in Figure 1, 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide resulted in a long-lasting effect on the left atrial Refractory period, which continued unaltered 180 minutes after completion of the infusion.

The following captions and markings have been made in the drawing:

1: duration of action on the refractory period of the left atrium of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] benzamide, 1 mg / kg infused over 100 minutes intravenously Y-axis:% of basal refractory X-axis: time in minutes

2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxy-pyridin-3-yl) -propyl] -benzamide control without active substance

Claims

claims

1. 2- (Butylr1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide of the formula I and its physiologically acceptable salts.

2. 2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide according to claim 1.

3. 2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide and / or its physiologically tolerable salts according to claim 1 and / or 2 for use as a drug.

4. Use of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) - propylj-benzamide and / or seiηe physiologically acceptable salts of claim 1 and / or 2 for the manufacture of a medicament for the therapy or prophylaxis of cardiac arrhythmias, supraventricular arrhythmias, atrial fibrillation and / or atrial flutter.

A pharmaceutical preparation for human or veterinary use containing an effective amount of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (δ-methoxypyridin-3-yl) -propyl] -benzamide of Formula I and / or its physiologically acceptable salts according to claim 1 and / or 2, together with pharmaceutically acceptable excipients and additives.

6. A pharmaceutical preparation for human or veterinary use containing an effective amount of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3-yl) -propyl] -benzamide of Formula I and / or its physiologically acceptable salts according to claim 1 and / or 2, together with pharmaceutically acceptable excipients and additives and optionally one or more other pharmacologically active substances.

7. 1 (R) - (6-methoxypyridin-3-yl) -propylamine

8. Use of 1 (R) - (6-methoxypyridin-3-yl) -propylamine as intermediate for the preparation of 2- (butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxy) pyridin-3-yl) -propyl] benzamide and / or its physiologically acceptable salts.