HK1086819A1 - 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 - Google Patents
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 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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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
The invention relates to 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of formula I, pharmaceutically acceptable salts thereof, their preparation and use, in particular in medicine.
The compounds of formula I and their pharmaceutically acceptable salts reduce the incidence of atrial arrhythmias with no effect or other side effects on the ventricles. The compounds of the invention and their pharmaceutically acceptable salts are therefore particularly suitable as novel antiarrhythmic active compounds, especially for the treatment and prophylaxis of atrial arrhythmias, for example Atrial Fibrillation (AF) or atrial flutter.
Atrial Fibrillation (AF) and atrial flutter are the most frequently occurring persistent arrhythmias. The incidence increases with age and often leads to fatal co-symptoms, such as cerebral infarction. AF affects approximately one million americans each year, and causes over eighty thousand americans to suffer a stroke each year. The current conventional class I and class III antiarrhythmic drugs, while reducing the recurrence rate of AF, can only be used restrictively due to their potential proarrhythmic (proarrhythmic) side effects. Thus, there is an urgent need to develop better drugs for the treatment of atrial arrhythmias (S.Nattel, am. Heart J.130, 1995, 1094-.
It has been found that most supraventricular arrhythmias are caused by "reentry" excitatory waves. This reentry occurs when the heart tissue has both a slow conductivity and a very short refractory period. Prolongation of the refractory period of the myocardium due to prolongation of action potentials is considered as a mechanism for terminating arrhythmia or preventing its formation (T.J.Colatsky et al, Drug Dev.Res.19, 1990, 129-140; "Potassium channel as a target for antiarrhythmic Drug action"). The length of the action potential essentially being determined by the variation of K+K of channel efflux cell+The degree of repolarization of the current. Here, "delayed rectification" IK is of great importance, consisting ofThree different components Ikr、IKsAnd IKurAnd (4) forming.
Most known class III antiarrhythmic drugs (e.g. dofetilide, E4031 and d-sotalol) block mainly or only the rapidly activated potassium channel IkrThis rapidly activated potassium channel can be detected in human ventricular and atrial cells. However, it has been demonstrated that: the increased risk of proarrhythmia at lower or normal heart rates is particularly observed with these compounds, and is known as "torsade de pointes" (D.M. roden, am.J. Cardiol.72, 1993, 44B-49B; "recent state of class III antiarrhythmic drug therapy"). In addition to this high risk in the case of lower heart rates, and even fatal in some cases, Ik was foundrBlockers are less active in the case of tachycardia ("negative use dependence"), which is particularly desirable in the case of tachycardia.
Delayed rectification IKurThe "very quickly" activated and very slowly deactivated components (corresponding to the kv1.5 channel) of the (ultrafast activation delay commutation) module play a particularly large role in the repolarization time of the human atrium. Therefore, and inhibit IkrOr IKsIn contrast, IK inhibitionurPotassium outward currents represent a particularly effective method of prolonging atrial action potentials and thereby terminating or preventing atrial arrhythmias.
Ik also occurs in human ventriclesrAnd IKsIn contrast, IKurPlays an important role in the human atrium rather than in the ventricle. For this reason, with blocking IkrOr IKsOn the contrary, when IK is suppressedurThe risk of ventricular proarrhythmic effects at current should be excluded from the outset (Z.Wang et al, Circuit. Res.73, 1993, 1061-The difference between currents outward of the muscle cells ").
However, to date, selective blockade of IKurAntiarrhythmic drugs for current or Kv1.5 channels 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 been described so far. The corresponding racemate thereof is mentioned as an example in patent application WO 0288073. The compounds of the formula I are distinguished by their surprising advantages.
It has now surprisingly been found that: the antiarrhythmic effect of the 2- (butyl-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of formula I of the present invention is excellent in the anesthetized pig model, while the activity of the corresponding 1(S) enantiomer is weaker. It was also found that: the compound of formula I has no effect on QTc intervals and no negative inotropic or hemodynamic side effects.
The experiment proves that: the compounds I are useful as novel antiarrhythmic agents with particularly advantageous safety. In particular, the compounds are suitable for the treatment of supraventricular arrhythmias, such as atrial fibrillation or atrial flutter. The compounds are useful for stopping ongoing atrial fibrillation or flutter, thereby regaining sinus rhythm (cardioversion). Moreover, it may reduce the susceptibility to the formation of new fibrillation (maintenance of sinus rhythm, prevention).
The present invention relates to 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of formula I and its pharmaceutically acceptable salts.
Since compound I contains a basic pyridine group, it can also be used in the form of pharmaceutically acceptable acid addition salts with inorganic or organic acids, such as hydrochloride, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate, fumarate, malate or gluconate salts and the like. Furthermore, the presence of a sulfonamido group also makes it possible to form alkali metal or alkaline earth metal salts, preferably sodium or potassium salts, or ammonium salts, for example with organic amines or amino acids. Pharmaceutically acceptable salts may be obtained from the compounds of formula I by conventional means, for example by combining with an acid or base in a solvent or dispersant, or by anion or cation exchange from other salts.
The free compound of formula I, 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide, is preferred.
The compounds of formula I can be obtained by different chemical methods, wherein two preparation possibilities are outlined in scheme 1. The coupling of the sulfonylaminobenzoic acid of the formula II with the amine of the formula III can be carried out directly from the acid in the presence of customary coupling reagents or, for example, from activated acid derivatives such as acid chlorides. When racemic 1- (6-methoxypyridin-3-yl) propylamine of formula III is used, separation of the enantiomers is carried out in the final stage, for example by chiral chromatography or conventional resolution. Alternatively, the desired enantiomer can be obtained directly by using 1(R) - (6-methoxypyridin-3-yl) propylamine of formula IIIa. Sulfonylaminobenzoic acids of formula II are prepared from the commercially available materials aminobenzoic acid and butylsulfonyl chloride according to methods known to those skilled in the art.
The present application likewise comprises the compound 1- (6-methoxypyridin-3-yl) propylamine of the formula III and its enantiomers, especially 1(R) - (6-methoxypyridin-3-yl) propylamine of the formula IIIa, as well as its use as an intermediate in the preparation of pharmaceutically active compounds such as 2- (butyl-1-sulfonamido) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide.
1- (6-methoxypyridin-3-yl) propylamine of formula III can be prepared from the commercially available compounds by different chemical methods, two preparation possibilities being summarized by way of example in scheme 2. In one aspect, 5-bromo-2-methoxypyridine is first metallated with butyl lithium, then reacted with propionitrile, and then reduced to the compound of formula III with sodium borohydride. Alternatively, 3-cyano-6-methoxypyridine is reacted with ethylmagnesium bromide, followed by reduction with sodium borohydride. Enantiomers are separated by conventional methods, such as chromatography in chiral phase, conventional resolution with the aid of chiral acids, or enzymatic methods.
The compounds of the formula I according to the invention and their physiologically tolerable salts can be used as medicaments on their own or in the form of pharmaceutical preparations in animals, preferably mammals, in particular humans. The invention also relates to compounds of the formula I and their physiologically tolerated salts for use as medicaments, to their use for the treatment and prophylaxis of cardiac arrhythmias, supraventricular arrhythmias, atrial fibrillation and/or atrial flutter, and to their use for producing medicaments for this purpose.
Furthermore, the invention relates to pharmaceutical preparations which, in addition to customary pharmaceutically nontoxic carriers and excipients, contain an effective dose of a compound of the formula I and/or its physiologically tolerable salts as active ingredient. Pharmaceutical preparations generally contain 0.1 to 90% by weight of a compound of the formula I and/or physiologically tolerated salts thereof. The pharmaceutical formulations may be prepared according to methods known to those skilled in the art. For this purpose, the compounds of the formula I and/or their physiologically tolerable salts can be brought into a suitable administration form or dosage form together with one or more solid or liquid pharmaceutical carriers and/or excipients and, if appropriate, other pharmaceutically active compounds, which can then be used as medicaments in human or veterinary medicine.
Medicaments comprising a compound of the formula I according to the invention and/or physiologically tolerable salts thereof can be administered, for example, orally, parenterally, for example intravenously, rectally, by inhalation or topically, the preferred administration depending on the individual situation, for example the particular clinical situation of the disease to be treated.
The person skilled in the art is familiar with excipients suitable for the desired pharmaceutical preparation on the basis of his/her expert knowledge. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, taste-masking agents, preservatives, solubilizers, agents for achieving depot action, buffer substances or colorants.
The compounds of the formula I can also be combined with other pharmaceutically active compounds in order to achieve a favourable therapeutic effect. Thus, in the treatment of cardiovascular diseases, a beneficial combination with substances having cardiovascular activity is possible. Possible combination partners for such a combination which is advantageous for cardiovascular diseases are, for example, other antiarrhythmic drugs, i.e.class I, class II or class III antiarrhythmic drugs, for example IKsOr IkrChannel blockers, such as dofetilide, or other hypotensive substances, such as ACE inhibitors (e.g. enalapril, captopril, ramipril), angiotensin antagonists and K+Channel activators, and alpha-receptor blockers, as well as sympathomimetic and adrenergic compounds, Na+/H+Exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other substances with positive inotropic activity, such as digitonin, or diuretics.
For oral administration, the active compounds are mixed with additives suitable therefor, such as carriers, stabilizers or inert diluents, and brought into a suitable administration form by customary methods, for example tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert carriers which can be used are, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. The preparation can be carried out here as dry granules and wet granules.
Suitable oily carriers or solvents are, for example, vegetable or animal oils, for example sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions, or mixtures thereof. Other excipients which are likewise used for other administration forms are, for example, polyethylene glycol and polypropylene glycol.
For subcutaneous, intramuscular or intravenous administration, the active compounds are formulated as solutions, suspensions or emulsions, if desired together with substances conventionally used therefor, such as solubilizers, emulsifiers or other excipients. The compounds of the formula I and their physiologically tolerable salts can be freeze-dried and the freeze-dried products obtained used, for example, for the production of injections or infusion solutions. Suitable solvents are, for example, water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, in addition to sugar solutions, for example glucose or mannitol solutions, or mixtures of a plurality of the mentioned solvents.
Pharmaceutical preparations which are suitable for administration as aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically tolerable salts in pharmaceutically nontoxic solvents, such as, in particular, ethanol or water or mixtures of such solvents. The formulations may additionally contain other pharmaceutical excipients, such as surfactants, emulsifiers and stabilizers, and propellants, if desired. The preparations generally contain about 0.1 to 10% by weight, in particular about 0.3 to 3% by weight, of active compound.
The dose at which the active compound of the formula I or a physiologically tolerable salt thereof is administered depends on the individual case and can be adjusted as usual to the individual case in order to achieve optimum action. It thus of course depends on the frequency of administration and on the nature and severity of the disease to be treated, on the sex, age, weight and individual response of the human or animal to be treated, and on whether the therapy is first aid or chronic or is prophylactic. In general, the daily dose of a compound of formula I is from 0.01mg/kg body weight to 100mg/kg body weight, preferably from 0.1mg/kg body weight to 20mg/kg body weight, when administered to a patient weighing about 75 kg. The dose may be administered in a single dose or in divided doses, e.g. two, three or four separate doses. Parenteral administration by injection or infusion, for example by intravenous continuous infusion, is likewise advantageous, in particular in the treatment of acute cases of cardiac arrhythmias, for example in intensive care units.
Experimental part
Preparation of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide a)2- (butyl-1-sulfonylamino) benzoic acid
20g (188mmol) of sodium carbonate are added to a suspension of 20g (146mmol) of 2-aminobenzoic acid in 250ml of water. 11.4g (72.8mmol) of butylsulfonyl chloride are then added dropwise and the reaction mixture is stirred at room temperature for 2 days. Acidifying with concentrated hydrochloric acid, stirring at room temperature for 3 hours, and suction-filtering the precipitated product. After drying in vacuo, 9.6g of 2- (butyl-1-sulfonylamino) benzoic acid are obtained.
b)1- (6-methoxypyridin-3-yl) -propylamines
Method 1
3ml (23.2mmol) of 5-bromo-2-methoxypyridine are added at-70 ℃ to a solution of 10.2ml of n-butyllithium (2.5M in hexane; 25.5mmol) in 50ml of diethyl ether. After 10 minutes, 1.4ml (19.5mmol) of propionitrile were added. After 2 hours at-70 ℃, the reaction mixture was slowly warmed to room temperature. Then 2.2g of sodium sulfate decahydrate were added and the mixture was stirred for 1 hour. Subsequently, 5g of magnesium sulfate was added, the salt was filtered off after brief stirring, and the filtrate was concentrated. The residue is dissolved in 70ml of methanol and 1.1g (28mmol) of sodium borohydride are added at 0 ℃. After stirring overnight, the reaction mixture was adjusted to pH 2 with concentrated HCl and concentrated on a rotary evaporator. The residue is treated with 10ml of water and extracted once with diethyl ether. The aqueous phase is then saturated with sodium bicarbonate, concentrated in vacuo, and the residue extracted with ethyl acetate. After drying and concentrating the ethyl acetate extract, 1.4g of racemized 1- (6-methoxypyridin-3-yl) -propylamine are obtained.
The enantiomers were separated by preparative HPLC on a Chiralpak ADH column (250 × 4.6 mm); eluent: heptane/ethanol/methanol 50: 1 with 0.1% diethylamine; temperature: 30 ℃; flow rate 1 ml/min.
First, 0.45g of 1(S) - (6-methoxypyridin-3-yl) -propylamine eluted at a retention time of 18.4 minutes. 0.42g of 1(R) - (6-methoxypyridin-3-yl) -propylamine eluted at a retention time of 21.0 minutes.
Method 2
170ml (170mmol) of a 1M solution of ethylmagnesium bromide in tetrahydrofuran are added dropwise at 0 ℃ under argon over the course of 30 minutes to a solution of 20g (150mmol) of 6-methoxynicotinonitrile and 0.62g (3.3mmol) of copper (I) iodide in 125ml of anhydrous tetrahydrofuran. After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred for an additional 3 hours. 200ml of methanol are then added dropwise at 5-10 ℃ and 11.3g (299mmol) of sodium borohydride are added in portions. After stirring overnight at room temperature, 300ml of water were added and the mixture was extracted 3 times with 250ml of ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated, and the residue is purified by chromatography. 5.5g of racemized 1- (6-methoxypyridin-3-yl) -propylamine are 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
To a solution of 8.0g (31.1mmol)2- (butyl-1-sulfonylamino) benzoic acid in 250ml tetrahydrofuran were added 4.4g (32.7mmol) 1-hydroxy-1 h-benzotriazole and 6.3g (32.7mmol) N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride and the reaction mixture was stirred for 90 minutes. A solution of 5.4g (32.7mmol) of racemized 1- (6-methoxypyridin-3-yl) -propylamine in 20ml of tetrahydrofuran was added dropwise and the mixture was stirred overnight. The reaction mixture was treated with 250ml of water and extracted with 300ml of ethyl acetate. The organic phase is extracted 5 times with 100ml each time of saturated sodium bicarbonate solution and then dried over magnesium sulfate. 9.0g of 2- (butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) propyl ] benzamide are obtained.
The enantiomers were separated by preparative HPLC on a Chiralpak ADH column (250 × 4.6 mm); eluent: heptane/ethanol/methanol 10: 1; temperature: 30 ℃; flow rate 1 ml/min.
First, 4.0g of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide was eluted at a retention time of 5.9 minutes. After a combined fraction, 3.0g of 2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl ] benzamide were eluted at a retention time of 7.2 minutes.
Method 2
In analogy to method 1, coupling of 0.41g (2.46mmol)1(R) - (6-methoxypyridin-3-yl) -propylamine and 0.64g (2.47mmol)2- (butyl-1-sulfonylamino) -benzoic acid in the presence of 1-hydroxy-1H-benzotriazole and N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride gave 0.9g 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide.
d)2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide
2g of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide obtained according to method 1 or 2 was dissolved in 9ml of isopropanol under heating, followed by addition of 8ml of warm water and slow cooling of the reaction mixture overnight. After suction filtration at 0 ℃ 1.5g of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide are obtained as colorless needle crystals; melting point 97 ℃. The absolute configuration is determined from a suitable single crystal by X-ray structural analysis.
Pharmacological study
The human Kv1.5 channel is expressed in Xenopus oocytes. For this purpose, oocytes are first isolated from Xenopus laevis (Xenopuslaevis) and then deslagged (defolliculate). RNA encoding Kv1.5 and synthesized in vitro was then injected into these oocytes. After the Kv1.5 protein is expressed for 1-7 days, the Kv1.5 current in the oocyte is measured by adopting a double-microelectrode voltage clamp technology. In this case, the Kv1.5 channel is activated as usual with a voltage jump to 0mV and 40mV for 500 ms. The bath was rinsed with a solution containing the following components: NaCl 96mM, KCl 2mM, CaCl2 1.8mM、MgCl21mM, HEPES 5mM (titrated with NaOH)To pH 7.4). These tests were all performed at room temperature. The following were used to obtain and analyze the data: gene Clamp Amplifier (Geneclamp Amplifier) (AxoInstructions, Foster City, USA) and MacLab D/A converter and software (ADInstructions, Castle Hill, Australia). By adding the substances of the invention to bath solutions of different concentrations. The effect of these substances was calculated as percent inhibition of the Kv1.5 control current, which Kv1.5 control current inhibition was obtained when the substance was not added to the solution. The data were then extrapolated using the Hill equation to determine the inhibitory concentration IC of each species50。
In this manner, the IC of the compounds listed below was determined50The values are as follows:
2- (butyl-1-sulfonylamino) -N- [1- (6-methoxypyridin-3-yl) propyl]Benzamide, in a mass ratio: IC (integrated circuit)50＝2.4μM
2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] of formula I]Benzamide, in a mass ratio: IC (integrated circuit)50＝10μM
2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl]Benzamide, in a mass ratio: IC (integrated circuit)50＝2.4μM
Study of refractory period and left atrial vulnerability in pigs
The effect of two enantiomers, 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of formula I and 2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl ] benzamide, on prolongation of the refractory period in the atrium of anaesthetised pigs and on the antiarrhythmic activity were studied and compared. During the course of the study, the refractory period of the left atrium was measured and the antiarrhythmic activity was recorded as described in the literature (Knobuch et al 2002. Nauyn-Schmiedberg's Arch. Pharmacol.366; 482. 487). Here the anti-arrhythmic effect relates to the suppression of arrhythmic episodes induced by extra stimuli (S2) previously placed in the left atrium (left atrial vulnerability).
Table 1 shows a comparison of the effect of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of formula I and 2- (butyl-1-sulfonylamino) -N- [1(S) - (6-methoxypyridin-3-yl) propyl ] benzamide on the refractory period of the left atrium after administration as a bolus of 3mg/kg to anaesthetised pigs and the antiarrhythmic activity.
The refractory period values are expressed as a percentage of the baseline value at 10 minutes post injection. The mean refractory period is given by the three rates (150, 200 and 250/min). From the results in table 1, it can be seen that the elongation of the refractory period for the R enantiomer is much longer than for the S enantiomer. It is possible to prevent 73.9% of arrhythmias by the R enantiomer, while the use of the S enantiomer only prevented the occurrence of 27% of arrhythmias.
Table 1:
| s enantiomer | R enantiomer | |||
| Mean value of | SEM | Mean value of | SEM | |
| Increase the refractory period% | 8.8％ | 3.4％ | 19％ | 4％ |
| Inhibition of cardiac arrhythmia% | 27.3％ | 2.4％ | 73.9％ | 11％ |
| n＝4 | n＝6 | |||
The duration of the effect of the substance on the refractory period can be determined in this test method by repeated measurements after administration of the drug. The pharmacological effect was determined at a dose of 1mg/kg by intravenous infusion of the R enantiomer for 100 minutes and at 280 minutes. As shown in FIG. 1, 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide exerts a long-lasting effect on the refractory period of the left atrium, which is maintained for 180 minutes after the end of infusion.
The following headings and notations in the drawings are given:
FIG. 1: duration of action of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide on the refractory period of the left atrium by intravenous infusion at 1mg/kg for 100 minutes
Y-axis: accounts for% of the refractory period baseline
An X axis: time (minutes)
Active-free control of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide
Claims (8)
1. 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of the formula I or a physiologically tolerable salt thereof,
2. 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide as claimed in claim 1.
3. Use of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide or a physiologically tolerable salt thereof as claimed in claim 1 or 2 for the preparation of a medicament for the treatment or prophylaxis of cardiac arrhythmias.
4. The use as claimed in claim 3, wherein the cardiac arrhythmia is supraventricular arrhythmia.
5. Use as claimed in claim 3 wherein the cardiac arrhythmia is atrial fibrillation or atrial flutter.
6. A human or veterinary pharmaceutical formulation for the treatment or prophylaxis of cardiac arrhythmias, comprising an effective amount of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide of the formula I as claimed in claim 1 or 2 or a physiologically tolerable salt thereof and pharmaceutically acceptable carriers and additives.
7.1(R) - (6-methoxypyridin-3-yl) -propylamine.
Use of 1(R) - (6-methoxypyridin-3-yl) -propylamine as intermediate in the preparation of 2- (butyl-1-sulfonylamino) -N- [1(R) - (6-methoxypyridin-3-yl) propyl ] benzamide or its physiologically tolerable salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10312073.4 | 2003-03-18 | ||
| DE10312073A DE10312073A1 (en) | 2003-03-18 | 2003-03-18 | 2- (Butyl-1-sulfonylamino) -N- [1 (R) - (6-methoxypyridin-3yl) -propyl] -benzamide, its use as a medicament and pharmaceutical compositions containing the same |
| PCT/EP2004/002247 WO2004083157A1 (en) | 2003-03-18 | 2004-03-05 | 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1086819A1 true HK1086819A1 (en) | 2006-09-29 |
| HK1086819B HK1086819B (en) | 2008-05-02 |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP2006520343A (en) | 2006-09-07 |
| TW200500342A (en) | 2005-01-01 |
| NZ542476A (en) | 2008-05-30 |
| NO20054472L (en) | 2005-09-27 |
| MY176510A (en) | 2020-08-12 |
| AR043622A1 (en) | 2005-08-03 |
| WO2004083157A1 (en) | 2004-09-30 |
| ZA200506328B (en) | 2006-04-26 |
| HRP20050815A2 (en) | 2006-09-30 |
| RU2005132163A (en) | 2006-04-10 |
| CA2519022A1 (en) | 2004-09-30 |
| PE20050307A1 (en) | 2005-06-08 |
| KR20050110681A (en) | 2005-11-23 |
| DE10312073A1 (en) | 2004-09-30 |
| MA27749A1 (en) | 2006-02-01 |
| BRPI0408441A (en) | 2006-04-04 |
| AU2004222137A1 (en) | 2004-09-30 |
| RS20050690A (en) | 2008-04-04 |
| CN100361943C (en) | 2008-01-16 |
| RU2333202C2 (en) | 2008-09-10 |
| CN1756728A (en) | 2006-04-05 |
| EP1606237A1 (en) | 2005-12-21 |
| MXPA05009763A (en) | 2006-01-27 |
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| Date | Code | Title | Description |
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| PC | Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee) |
Effective date: 20120305 |