KR20050110681A - 2-(butyl-1-sulfonylamino)-n-[1(r)-(6-methoxypyridin-3-yl)-propyl]-benzamide, the use thereof in the form of drug and pharmaceutical preparations containing said compound - Google Patents

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

2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) -propyl] -benzamide, its use as a drug, and pharmaceutical preparations containing the same {2- (Butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) -propyl] -benzamide, the use particular in the form of drug and pharmaceutical preparations containing said compound}

2- (butyl-1- Sulfonylamino ) -N- [1 (R)-(6- Methoxypyridine -3-yl) -propyl] Benzamide  Produce

a) 2- (butyl-1- Sulfonylamino Benzoic acid

20 g (188 mmol) of sodium carbonate was added to a suspension of 20 g (146 mmol) of 2-aminobenzoic acid in 250 ml of water. Then 11.4 g (72.8 mmol) of butylsulfonyl chloride were added dropwise and the reaction mixture was stirred at room temperature for 2 days. It was acidified with concentrated hydrochloric acid, stirred at room temperature for 3 hours, 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- Methoxypyridine -3 days) Propylamine

Method 1

3 ml (23.2 mmol) of 5-bromo-2-methoxypyridine is added 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. It was. After 10 minutes, 1.4 ml (19.5 mmol) propionitrile were added. After 2 hours at -70 ° C, the reaction mixture was slowly warmed to room temperature. Then 2.2 g sodium sulfate decahydrate was added and the mixture was stirred for 1 hour. 5 g of sodium sulfate were added successively, then stirred for a while, then the salts were filtered off and the filtrate was concentrated. The residue was dissolved in 70 ml of methanol and 1.1 g (28 mmol) sodium borohydride were added at 0 ° C. After stirring overnight, the reaction mixture was adjusted to pH 2 with concentrated hydrochloric acid and concentrated on a rotary evaporator. The residue was treated with 10 ml of water and extracted once with diethyl ether. The aqueous phase was then saturated with sodium hydrogen carbonate, concentrated in vacuo and the residue extracted with ethyl acetate. After drying and concentrating the ethyl acetate extract, 1.4 g of racemic 1- (6-methoxypyridin-3-yl) propylamine was obtained.

Preparative HPLC (Chiralpak ADH column (250 x 4.6 mm); eluent: heptane / ethanol / methanol 50: 1: 1 with 0.1% diethylamine; temperature: 30 ° C .; flow rate 1 ml / min). First, 0.45 g of 1 (S)-(6-methoxypyridin-3-yl) propylamine was eluted at a residence time of 18.4 minutes. 0.42 g of 1 (R)-(6-methoxypyridin-3-yl) propylamine was then eluted at a residence time of 21.0 minutes.

Method 2

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

Method 1

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 were charged with 250 ml of tetrahydro To a solution of 8.0 g (31.1 mmol) of 2- (butyl-1-sulfonylamino) benzoic acid in furan, the reaction mixture was stirred for 90 minutes. Then a solution of 5.4 g (32.7 mmol) of racemic 1- (6-methoxypyridin-3-yl) propylamine in 20 ml of tetrahydrofuran was added dropwise and the mixture was 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 five times with 100 ml of saturated sodium bicarbonate solution each time and then dried over magnesium sulfate. 9.0 g of 2- (butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) propyl] benzamide were obtained.

Ethaneomer was purified using preparative HPLC (Chiralpak ADH column (250 × 4.6 mm); eluent: heptane / ethanol / methanol 10: 1: 1; temperature: 30 ° C .; flow rate 1 ml / min). First, 4.0 g of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) -propyl] benzamide eluted at a residence time of 5.9 minutes. . After the mixed fractions, 3.0 g of 2- (butyl-1-sulfonylamino) -N- [1 (S)-(6-methoxypyridin-3-yl) -propyl] benzamide was added in 7.2 minutes. Obtained at residence time.

Method 2

0.9 g of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] -benzamide, similar to Method 1, was treated with 1-hydro Coupling in the presence of oxy-1H-benzotriazole and N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride, 0.41 g (2.46 mmol) of 1 (R)-(6-meth Obtained from oxypyridin-3-yl) propylamine and 0.64 g (2.47 mmol) of 2- (butyl-1-sulfonylamino) -benzoic acid.

d) 2- (butyl-1- Sulfonylamino ) -N- [1 (R)-(6- Methoxypyridine -3-yl) propyl] Benzamide

2 g of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] -benzamide obtained according to Method 1 or 2 were heated Under 9 ml of isopropanol, then 8 ml of warm water were added and the reaction mixture was cooled slowly overnight. After suction filtration at 0 ° C., 1.5 g of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide were obtained as needle crystals. It was obtained (melting point 97 ° C.). Absolute coordination was confirmed from appropriate single crystals by x-ray structure analysis.

Pharmacological Research

Human Kv 1.5 channels were expressed in Xenopus oocytes. For this purpose, oocytes were first isolated from Xenopus laevis and the follicles were removed. RNAs encoding Kv 1.5 synthesized in vitro were then injected into these oocytes. After expressing Kv 1.5 protein for 1-7 days, Kv 1.5 current was measured in the oocytes using two microelectrode voltage clamp techniques. In this case the Kv 1.5 channel was typically activated using voltage jumps to 0 mV and 40 mV lasting 500 ms. The bath was washed using a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl ₂ 1.8 mM, MgCl ₂ 1 mM, HEPES 5 mM (titrated to pH 7.4 with NaOH). These experiments were performed at room temperature. The instrument described below was used for data acquisition and analysis: Geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D / A converters and software (ADInstruments, Castle Hill, Australia). The materials according to the invention were tested by adding them to different concentrations of the bath solution. The effect of this material was calculated as% inhibition of Kv 1.5 control current obtained when no material was added to the solution. The data were then extrapolated using the Hill equation to determine the inhibitory concentration IC ₅₀ for each material.

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

2- (butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) propyl] benzamide: IC 50 = 2.4 μM

2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide of formula I: IC 50 = 10 μΜ

2- (butyl-1-sulfonylamino) -N- [1 (S)-(6-methoxypyridin-3-yl) propyl] benzamide: IC 50 = 2.4 μM

Pig Refractory  Of the left and left atrium vulnerabilities

Two enantiomers 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide and 2- (butyl-1) of formula (I) -Sulfonylamino) -N- [1 (S)-(6-methoxypyridin-3-yl) propyl] benzamide was investigated and regarding the extension of refractory and antiarrhythmic activity to the atria of anesthetized pigs Compared. In this process, Knobloch et al. 2002. Naunyn-Schmiedberg's Arch. Pharmacol. 366; 482-487, the left atrium refractory was measured and antiarrhythmic activity was recorded. Antiarrhythmic action herein relates to the inhibition of the occurrence of arrhythmia episodes induced by hyper-stimulation (S2) prematurely imparted to the left atrium (= left atrial fragility).

2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxy) of Formula I for left atrial refractory and antiarrhythmic activity in anesthetized pigs after bolus administration of 3 mg / kg Comparison of the action of pyridin-3-yl) propyl] benzamide and 2- (butyl-1-sulfonylamino) -N- [1 (S)-(6-methoxypyridin-3-yl) propyl] benzamide Is presented in Table 1. The refractory value is expressed as% of the reference value 10 minutes after injection. The average value of the noncondensation is given from three speeds (150, 200 and 250 / min). From the results summarized in Table 1, it can be seen that the R enantiomer extends significantly higher refractors than the S enantiomer. While 73.9% of arrhythmias induced by R enantiomers could be prevented, the use of S enantiomers inhibits the development of arrhythmias to only 27%.

S enantiomer R enantiomer Average value SEM Average value SEM % Increase in refractory 8.8% 3.4% 19% 4% % Inhibition of arrhythmia 27.3% 2.4% 73.9% 11% n = 4 n = 6

Through repeated measurements after the administration of the substance, the duration of the action of the substance on the refractory can be determined during the course of the experiment. R enantiomer was injected intravenously over 100 minutes at a dose of 1 mg / kg and pharmacological action was measured over 280 minutes. As shown in FIG. 1, 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide has long-term response to left atrial refractory It induced a sustained action, which also remained unchanged for 180 minutes after the infusion was terminated.

The following description and representations have been used in the drawings.

1: Inject 1 mg / kg of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide intravenously over 100 minutes Duration of action on the left atrium

Y axis:% of reference inconsistency

X axis: time (minutes)

2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide

Control without active substance

The present invention relates to 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide of formula I and pharmaceutically acceptable salts thereof, To its preparation and in particular its use as a medicament.

Compounds of formula (I) and pharmaceutically acceptable salts thereof can reduce the incidence of atrial arrhythmia without acting on the ventricles or involving other side effects. Thus, the compounds according to the invention and pharmaceutically acceptable salts thereof are particularly suitable as novel antiarrhythmic active compounds for the treatment and prevention of atrial arrhythmias such as atrial fibrillation (AF) or atrial fluttering.

Atrial fibrillation and atrial fibrillation are the most frequent and lasting cardiac arrhythmias. The incidence increases with age and often causes fatal collateral symptoms such as cerebral infarction. AF suffers about 1 million Americans each year and causes more than 80,000 strokes each year in the United States. Currently used antiarrhythmic agents of type I and III reduce the recurrence rate of AF, but are only used on a limited basis because of their potential proarrhythmic side effects. Therefore, there is a huge medical need to develop 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"].

Most ventricular arrhythmias have been found to correspond to "reentry" excitement. This reentrancy occurs when the heart tissue has a slow conductivity and at the same time has a very short incoherence. Increasing myocardial retardation due to prolongation of action potentials is recognized as a mechanism for ending arrhythmia or preventing its formation. See TJ Colatsky et al., Drug Dev. Res. 19, 1990, 129-140; "Potassium channels as targets for antiarrhythmic drug action"]. The magnitude of the action potential is substantially determined by the degree of repolarization of the K ⁺ current flowing out of the cell through the various K ⁺ channels. Of particular importance here are the "delayed rectifier" IK consisting of three different components IK _r , IK _s and IK _ur .

The most well known type III antiarrhythmic agents (eg, dofetilide, E4031 and d-sotalol) block predominantly or exclusively the rapidly activated potassium channel IK _r, which channels It can be found in both ventricular and atrial cells. However, these compounds are associated with increased risk of chemotaxis at low or normal heart rates, in particular DM Roden, Am. J. Cardiol. 72, 1993, 44B 49B; "Current status of class III antiarrhythmic drug therapy"] causes arrhythmia, described as "torsades de pointes". In addition to this high risk at low heartbeats and in some cases fatal risk, a decrease in activity under tachycardia conditions, in which an effect is particularly required, has been found in IK _r blockers (“negative use dependence”).

The component IK _ur (= super-fast activation delayed rectifier), which activates the “particularly rapidly” and very slowly inactivates of delayed rectifiers, corresponds to the Kv 1.5 channel and plays a particularly important role with respect to the timing of repolarization of the human atria. Thus, inhibition of outwardly directed IK _ur potassium current provides a particularly effective method for prolonging atrial action potential and thus ending or preventing atrial arrhythmias, as compared to inhibition of IK _r or IK _s . .

Unlike IK _r and IK _s , which are also present in the human ventricles, IK _ur actually plays an important role in the human atria, but not in the ventricles. For this reason, unlike the blocking of IK _r or IK _s , when inhibiting IK _ur currents, the risk of arrhythmia-induced action on the ventricles is excluded from the beginning. Z. Wang et al, Circ. Res. 73, 1993, 1061-1076: "Sustained Depolarisation-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 Amos et al., J. Physiol. 491, 1996, 31-50: "Differences between outward currents of human atrial and subepicardial ventricular myocytes"].

However, antiarrhythmic agents acting through selective blocking of IK _ur current or Kv 1.5 channel are not commercially available until now.

The enantiomer 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) -propyl] benzamide claimed herein has never been described. Corresponding racemates are mentioned by way of example in patent application WO 0288073. Compounds of formula (I) are distinguished by surprising advantages.

Surprisingly, according to the present invention, 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide of the formula (I) according to the present invention The antiarrhythmic effect was excellent in the model using anesthetized pigs, and the corresponding 1 (S) enantiomer was found to have weaker activity. In addition, it has been found that the compounds of formula (I) have no effect on the QTc interval and do not have reduced contractile force or hemodynamic side effects.

The experiments confirmed that the compounds of formula I can be used as novel antiarrhythmics, which are particularly advantageous in terms of safety. In particular, the present compounds are suitable for the treatment of ventricular arrhythmias such as atrial fibrillation or atrial fibrillation. The compounds can be used to terminate existing atrial fibrillation or rhythm for the return of sinus rhythm (heart rhythm conversion). It also reduces the susceptibility to the formation of new fibrillation phenomena (holding, preventing rhythms).

The present invention relates to 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide of formula I and pharmaceutically acceptable salts thereof. It is about.

Since the compound of formula (I) contains basic pyridine radicals, it is in the form of pharmaceutically acceptable acid addition salts with inorganic or organic acids, for example hydrochloride, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate , Fumarate, malate, gluconide and the like. In addition, due to the presence of sulfonamide groups, it is possible to form salts with alkali or alkaline earth metal salts, preferably sodium or potassium salts, or ammonium salts, for example with organic amines or amino acids. Pharmaceutically acceptable salts can be obtained from the compounds of formula (I) by conventional processes, for example in combination with acids or bases in solvents or dispersants, or else from other salts by anion or cation exchange. .

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

Compounds of formula (I) can be prepared by different chemical processes, two of which are feasible in the process are summarized in Scheme 1. The coupling reaction of sulfonylaminobenzoic acid of formula (II) with an amine of formula (III) can be carried out directly from the acid in the presence of a conventional coupling reagent, or for example an activated acid, for example an acid chloride. Can be performed from In case of using racemic 1- (6-methoxypyridin-3-yl) propylamine of the formula (III), the cleavage to enantiomer is carried out in a final step, for example by chiral chromatography or conventional cleavage. . Alternatively, the desired enantiomer can be obtained directly by using 1 (R)-(6-methoxypyridin-3-yl) -propylamine of formula IIIa. Sulfonylaminobenzoic acid of formula (II) is prepared from commercially available aminobenzoic acid and butylsulfonyl chloride according to methods known to those skilled in the art.

The present application likewise discloses compound 1- (6-methoxypyridin-3-yl) -propylamine of formula III and enantiomers thereof, in particular 1 (R)-(6-methoxypyridine of formula IIIa, used as intermediate -3-yl) propylamine, and pharmaceutically active compounds such as 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] Its use for the preparation of benzamides.

1- (6-methoxypyridin-3-yl) propylamine of formula III can be prepared from commercially available compounds by different chemical processes, two of which are feasible in the process are summarized in Scheme 2. . On the other hand, 5-bromo-2-methoxypyridine can first be metallized using butyllithium wool, then reacted with propionitrile and then reduced to the compound of formula III using sodium borohydride. Alternatively, 3-cyano-6-methoxypyridine can be reacted with ethylmagnesium bromide and then reduced using sodium borohydride. The cleavage into enantiomers can be carried out by conventional methods such as chromatography on chiral, conventional cleavage with chiral acid, or enzymatic methods.

The compounds of formula (I) or physiologically acceptable salts thereof according to the invention can be used as medicaments to animals, preferably mammals, in particular humans, by themselves or in the form of pharmaceutical preparations. The present invention also relates to the use of the compounds of formula (I) and their physiologically acceptable salts, cardiac arrhythmias, ventricular arrhythmias and / or atrial fibrillation and / or atrial fibrillation for use as a medicament, and It relates to the use thereof in the manufacture of a medicament for the treatment and prophylaxis. The invention also relates to pharmaceutical preparations which contain, in addition to conventional pharmaceutically non-toxic vehicles and excipients, an effective amount of a compound of formula (I) and / or a physiologically acceptable salt thereof as an active ingredient. The pharmaceutical preparations typically contain 0.1 to 90% by weight of the compound of formula (I) and / or physiologically acceptable salts thereof. The pharmaceutical formulations may be prepared according to methods known to those skilled in the art. To this end, a compound of formula (I) and / or a physiologically acceptable salt thereof, in combination with one or more solid or liquid pharmaceutical vehicles and / or excipients, optionally with other pharmaceutically active compounds, in an appropriate dosage form or It may be prepared in a dosage form and may be used as a human or veterinary agent.

Pharmaceuticals containing a compound of formula (I) and / or physiologically acceptable salts thereof according to the invention can be administered, for example, orally, parenterally, such as intravenous, rectal, inhaled, or topically. Preferred dosing depends on the individual case, for example on the clinical condition of the disease to be treated.

Those skilled in the art know, based on their expertise, excipients suitable for the desired pharmaceutical formulation. In addition to solvents, gel-forming agents, suppository bases, tablet excipients and other active compound carriers, for example antioxidants, dispersants, emulsifiers, antifoams, taste modifiers, preservatives, solubilizers, for achieving the depot effect Formulations, buffer materials or colorants can be used.

In order to achieve a beneficial therapeutic effect, compounds of formula (I) can also be combined with other pharmaceutically active compounds. Thus, in the treatment of cardiovascular diseases, combination with substances having cardiovascular activity may be advantageous. Examples of possible combination partners of this type that are beneficial for cardiovascular disease include other antiarrhythmic agents, such as type I, type II or type III arrhythmia, such as IK _s or IK _r channel blockers (eg dofetilide), or additionally Low blood pressure substances, such as ACE inhibitors (e.g. enalapril, captopril, ramipril), angiotensin antagonists and K ⁺ channel activators, and alpha-receptor blockers, as well as sympathetic Neuroexciting compounds and compounds with adenerine activity, and Na ⁺ / H ⁺ exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors, and other substances with accelerated contractile activity, such as digitalis glycosides, or Diuretics.

In the case of oral dosage forms, the active compounds are mixed with suitable additives, for example vehicles, stabilizers, or inert diluents, and suitable dosage forms, for example tablets, epidermal tablets, hard gelatin capsules, using conventional methods , Aqueous, alcoholic or oily solutions. Examples of inert carriers that can be used include gum arabic, magnesia, magnesium carbonate, magnesium phosphate, lactose, glucose or starch, in particular corn starch. The formulations herein can be carried out as both anhydrous granules and wet granules. Examples of suitable oily vehicles or solvents include vegetable or animal oils such as sunflower oil or cod liver oil. Examples of suitable solvents of aqueous or alcoholic solutions include water, ethanol or sugar solutions, or mixtures thereof. In addition, examples of excipients for other dosage forms include polyethylene glycol and polypropylene glycol.

In the case of subcutaneous, intramuscular or intravenous administration, the active compounds may be prepared as solutions, suspensions or emulsions, optionally with conventional substances for this purpose, for example solubilizers, emulsifiers or additional excipients. have. The compounds of formula (I) and physiologically acceptable salts thereof can also be lyophilized and the lyophilisates obtained can be used, for example, in the preparation of injectable or injectable preparations. Examples of suitable solvents are water, physiological saline or alcohols such as ethanol, propanol, glycerol, further sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Examples of pharmaceutical formulations suitable for administration in the form of aerosols or sprays include solutions of the compounds of formula (I) or physiologically acceptable salts thereof in pharmaceutically nontoxic solvents such as in particular ethanol or water or mixtures of these solvents. , Suspensions or emulsions. If desired, the formulation may further contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and propellants. Such formulations usually contain the active compound at a concentration of about 0.1 to 10, in particular about 0.3 to 3% by weight.

The dosage of the active compound of formula (I) or a physiologically acceptable salt thereof will vary from case to case and will typically be appropriate for the pathology of the individual case for optimal action. Thus, this is naturally dependent on the frequency of administration, as well as the nature and severity of the disease to be treated, and the sex, age, weight and individual responsiveness of the person or animal to be treated, and whether the treatment is urgent or continuous or precautions should be taken. Different. Typically, when administered to a patient weighing about 75 kg, the daily dose of the compound of formula I is between 0.01 mg / kg body weight and 100 mg / kg body weight, preferably 0.1 mg / kg body weight. To 20 mg / kg body weight. The dose may be administered in one unit dose form or divided into multiple, for example 2, 3 or 4 unit doses. In particular, in the case of treating acute cases of cardiac arrhythmias, for example in an intensive care unit, parenteral administration by injection or infusion, eg intravenous continuous infusion, may be advantageous.

Claims (8)

2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide of formula I and its physiologically acceptable salts. Formula I The 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide of claim 1. 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide according to claim 1 or 2 for use as a medicament and And / or physiologically acceptable salts thereof. 2- (butyl-1-sulfonylamino) -N- [according to claim 1 or 2 in the manufacture of a medicament for the treatment or prevention of cardiac arrhythmias, ventricular arrhythmias, atrial fibrillation and / or atrial fibrillation. Use of 1 (R)-(6-methoxypyridin-3-yl) -propyl] benzamide and / or physiologically acceptable salts thereof. An effective amount of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide according to claim 1 or 2 and A human or veterinary pharmaceutical formulation comprising / or a physiologically acceptable salt thereof together with a pharmaceutically acceptable vehicle and additive. An effective amount of 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide according to claim 1 or 2 and A human or veterinary pharmaceutical formulation comprising / or a physiologically acceptable salt thereof together with a pharmaceutically acceptable vehicle and additives, and optionally one or more other pharmacologically active compounds. 1 (R)-(6-methoxypyridin-3-yl) propylamine. Intermediates for preparing 2- (butyl-1-sulfonylamino) -N- [1 (R)-(6-methoxypyridin-3-yl) propyl] benzamide and / or physiologically acceptable salts thereof Use of 1 (R)-(6-methoxypyridin-3-yl) propylamine as.