MXPA00005768A - Novel antiarrhythmic compounds - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein R1 and R2, independently from each other, mean hydrogen, halogen or C1-4 alkyl group;R3, R4 and R5, independently from each other, stand for hydrogen or C1-4 alkyl group;R6 represents hydrogen, C1-4 alkyl or benzyl group;R7 means nitro group or amino group optionally monosubstituted by C1-4 alkyl, benzoyl, C1-4 alkylcarbonyl, C1-4 alkylsulfonyl, C1-4 alkylcarbamoyl or C1-4 alkylthiocarbamoyl group;both n and m are 0 or 1, with the proviso that R2 is different from hydrogen, when R1 is hydrogen, as well as stereoisomers or mixtures of stereoisomers thereof, acid addition salts thereof and hydrates, prodrugs and metabolites of all these compounds. The invention relates also to the pharmaceutical compositions comprising the above compounds. The compounds according to the invention possess valuable antiarrhythmic effect.

Description

NEW ANTIARRHYTHMIC COMPOUNDS Field of the Invention The present invention relates to novel phenoxyalkylamine derivatives that are active as antiarrhythmics, possessing a double point of attack. More particularly, the present invention relates to novel phenoxyalkylamine derivatives of the formula (I): and its salts, as well as the pharmaceutical compositions containing these compounds. It is known that cardiac arrhythmias represent one of the most severe fields of cardiovascular diseases. Of these, the most serious is cardiac ventricular fibrillation, which is the most common intermediate cause of sudden cardiac death and leads to approximately 400,000 deaths in a year in the United States alone. Atrial fibrillation also accompanied by serious complications occurs in approximately one million people. The most widely used arrhythmia treatment method is drug therapy. However, currently available agents can not be considered as the best solution: their use can be significantly limited by their serious side effects. From this point of view, the negative results of two series of comprehensive clinical investigations [CAST I and CAST II, The CAST Investigators, N. Engl. J. Med. 321, 406 (1989) and 327, 227 (1992)] bringing to light that some of the so-called Class IC antiarrhythmic agents, with slow recovery kinetics, which inhibit the maximum amount of repolarization of the action potential from the heart; for example, the sodium channel, impaired the chances of survival of patients recovering from myocardial infarctions [For example, the article by AO Grant Jr., and NC Durham in Am. Heart J. 123, page 1130 ( 1992)]. These unfavorable results can be related to the pro-arrhythmic effect (for example, provocation of arrhythmia) and the negative inotropic effect [awakening (producing) the cardiac functioning] of the antiarrhythmic agents of class IC medications. Subsequently, it turned in a similar manner to the class III antiarrhythmic agents, increasingly attracting attention at the beginning of the 90s [which prolong the duration of the action potential and therefore the refractory period cash (abbreviated ERP)] are not free from dangerous side effects; and the clinical trials of d-sotalol (chemically hydrochloride dN- [4- [1-hydroxy-2- (1-methylethylamino) -ethyl] phenyl] methanesulfonamide) as a prototype of class III were still interrupted in the treatment group due to the increase in mortality attributable to the pro-arrhythmic effect [see, for example, the article by P. Mátyus, A. Varro, J. Gy. Papp and associates: in Med. Res. Rev. 17, 427 (1997)]. There are dangers or limits, respectively, to the use of two additional classes of antiarrhythmic drugs (II and IV) as well as two other subgroups (IA and 1B) of the blockade of the sodium channel of Class I (especially in the case of Classes IV and IA).

Even on the basis of those mentioned above, it is obvious that there is a great demand for a new type of safe, but simultaneously adequate, antiarrhythmic active agent. The objective of the present invention is to develop an active agent and the composition, respectively, covering these requirements. A number of phenoxyalkylamine derivatives are known in the literature. However, both their chemical structures and their biological effects are different from the compounds of the formula (I) of the present invention. Only the references describing the substances having the structures most related to the compounds according to the present invention are summarized below. Patent EP 245,997 refers to bis (aralkyl) amines and phenoxyalkylamine derivatives, effective against arrhythmia, of which some compounds exert a positive inotropic action as well. According to the authors, these compounds are selective antiarrhythmics of class III. The derivative of the formula (VI) it was found that the most active are those that contain the methanesulfonamido group in 4 positions of both phenyl rings. Japanese published patent application No. 06,107,614 describes compounds that are not within the scope of the present invention, which can be characterized by the formula (I), wherein R 1, R 2 and R 3 signify hydrogen, both n and m are 0, or one of them is 1; R 4 means hydrogen, alkyl, formyl or alkylthiocarbamoyl groups and R 7 represents an amino group substituted by p-chlorobenzenesulfonyl, 1,3,6-triisopropylbenzenesulfonyl, 8-quinolinesulfonyl, 1-naphthoyl or 2-pyridinecarbonyl group. According to the description of these compounds, they are endowed with anti-ulcer effects. In US Pat. No. 4,044,150, the 4 '- [1-phenylethyl) amino] ethyl] -methanesulfonanilide of the formula (VII) is described and the salts thereof, which have a chemical structure representing approximately a part of the compounds of the present invention. According to the authors of this patent, these substances are β-andrenergic receptor blocking agents, and so they can be useful as antihypertensive agents. Phenoxyalkylamino derivatives that have chemical structures which are kept close to the compounds of the present invention are known from GB 2,088,873, wherein the phenoxy group can be mono- or bisubstituted by hydrogen, halogen, hydroxyl or alkoxy groups , while the phenyl group (s) at the other end of the alkylaminoalkyl chain can be di-, or trisubstituted by a para-hydroxyl or amino and / or meta-halogen group (s) as well as trifluoromethyl, cyano or nitro groups. According to the authors, these compounds act on the heart and circulation, more particularly they exert antihypertensive, antiarrhythmic and / or cardiotonic effects. However, the biological information provided in the description confirms only the positive notrópica efficiency of the compounds. Finally, it was mentioned as a point of interest that the compounds analogous to the substances of the formula (I) of the present invention, the phenoxy group which is substituted by an acylamino group, and the phenyl group on the other side of the alkylaminoalkyl chain is substituted by a C 1-4 alkyl or alkoxy and / or halogen group (which, consequently, contains an inverse substitution to the compounds of the present invention) has an antitumor effect (EP 494,623). During our investigations it has surprisingly been discovered that the compounds of the formula (I) possess a strong antiarrhythmic action and that they do not exhibit adverse side effects. In its mode of action, the effects of type 1 B and III are associated with the result in a very favorable antiarrhythmic action of the spectrum wider than those that characterize the individual components of action; This is a consequence of the combined mechanism. Simultaneously, it has been shown that the compounds of the formula (I) are free of serious adverse effects, which are characteristic of classes I and III. These favorable pharmacological properties of the compounds of the formula (I) are particularly surprising in view of the information found in the literature. That is, with respect to the structural chemical requirements of the antiarrhythmics of classes IB and III, there is a view that the antiarrhythmic action of class IB is characteristic of the ortho-disubstituted (or isosteric) phenoxyalkylamino systems they contain a short alkyl chain and an amino substituent with small steric demand (see, for example, tocainide, lidocaine); while compounds that exert a strong effect of class III are characterized by a structure containing two phenyl groups connected by a relatively long chain, wherein both of the phenyl groups have substituents that attract para-positioned electrons, for example located symmetrically [for a detailed analysis of structure-effect relationships, see for example, the article by P. Mátyus, A, Varró, J. Gy. Papp and associates: in Med. Res. Rev. 17, page 427 (1997)]. Consequently, it is surprising even to one skilled in the art that the compounds of the formula (I) according to the present invention, which have a structure fundamentally different from the typical representatives of the antiarrhythmics of both classes IB III, have an effect significant antiarrhythmic association of the effects of both types IB and III while they are free of negative pro-arrhythmic or inotropic effects. It is well known from the literature that compounds with a double point of attack are very important for pharmaceutical chemistry [see for example: "The Practice of Medicinal Chemistry" pages 261 to 293, of Ed. CG Wermuth, Academic Press, London (1996)]. In the present case, the combination of the two mechanisms of action of the aforementioned antiarrhythmics is still more advantageous than usual, because it results in qualitatively new, extremely favorable properties; that is, due to the simultaneous presence of both components of action, the compounds of the formula (I), do not exhibit effects either pro-arrhythmic or negative inotropic. Otherwise, this combination of effects incorporated in one and the same molecule is more preferred from the standpoints of pharmacokinetics and drug safety, also, as compared to the combination of both individual molecules.

Adding it from the Invention When taken together with the consideration that their toxicity is low, the compounds of the formula (I) can be considered as safe antiarrhythmic drugs, candidates of a new type with a broad spectrum of activities. Thus, the present invention relates to compounds of the formula (I) wherein R and R 2, independently of one another, mean a hydrogen, halogen or C 1-4 alkyl group; R3, R4 and R5 represent, independently of one another, a hydrogen or C1-4 alkyl group; R6 represents a hydrogen, C1-4 alkyl or benzyl group; R7 means a nitro group or amino group optionally monosubstituted by a C-, benzoyl-, C 1-4 -alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylcarbamoyl or alkylthiocarbamoyl C- group: both of n and m are 0 or 1; with the proviso that R2 is different from hydrogen, when R1 is hydrogen; as well as the stereoisomers or mixtures of stereoisomers thereof, acid addition salts thereof and hydrates, prodrugs and metabolites of all these compounds. In the compounds of the present invention, the alkyl groups may have a straight or branched carbon chain; Halogen can mean bromide, chloride or fluoride. According to the above, in the formula (I) R1 and R2, independently represent one of the other, a methyl, ethyl, n-propyl, isopropyl or butyl group; also fluoride, chloride or bromide. In the case where one of R1 and R2 means hydrogen, the other must be different from hydrogen. Therefore, the substituted phenoxy group in the formula (I) can be, for example, a 2,3-dimethylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy, 2,6-dimethylphenoxy, 2,6- diethylphenoxy, 2-ethyl-6-methylphenoxyl, 2-chloro-6-methylphenoxy, 2-6, dichlorophenoxy, 2-bromo-6-methylphenoxyl, 2,6-dibromofenxyl, 2-bromo-4-chlorofenzyl, 2-methylphenoxy, 2-ethylphenoxy, 2-isopropylphenoxy, 2-chlorophenoxy, 2-bromophenoxy or 2-fluorophenoxy. R3, R4, R5 and R6 represent, independently of one another, a hydrogen, methyl, ethyl, n-propyl, isopropyl or butyl group; additionally, R6 can mean a benzyl group; R7 may, for example, represent a group of nitro, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, acetylamino, propionylamino, isopropionylamino, butanoylamino, benzoylamino, methanesulfonamido, ethanesulfonamido, n-propopanesulfonamido, isopropylsulfonamido, butanesulfonamido, methylureido, ethylureido, n-propylureido , isopropylureido, methylthioureido or ethylthioureido. An advantageous group of the compounds of the formula (I) according to the present invention is represented by substances, wherein R 1 signifies an alkyl group, and from R 2 to R 7 and n are as defined above and m is 0. Another group Preferred of compounds of the present invention comprises compounds of the formula (I), wherein R 1 and R 2 together represent a 2,6-dialkyl group, R 3 and / or R 6 means (n) an alkyl group, R 7 and n are as they were previously defined and m is 0.

Detailed Description of the Invention The compounds of the formula (I) according to the present invention can be prepared using various methods known per se. a) For the preparation of compounds of the formula (I), wherein R1 and R2 mean an alkyl or halogen group, or one of them means hydrogen, R3, R4, R5, R6, n and m are as defined above and R7 represents a nitro group, for example a compound of the formula (II) wherein R1, R2, R3, R4, R5, R6, n and m are as defined above, are reactivated with 4-nitrophenethyl bromide. This reaction can be carried out under heating without any solvent or in various solvents, for example, isopropanol, butanol or acetonitrile. A part of the amino compounds of the formula (II) used as starting materials are known in the literature (for example in patents BE 626,725, US 3,659,019). The compounds of the formula (II) not described in the literature up to now can be prepared by known methods. The preparation of novel compounds of the formula (II) which start from the compounds of the formula (V) they are described in the Examples. b) For the preparation of compounds of the formula (I), wherein R1 and R2 represent an alkyl group or one of them is hydrogen, R3, R4, R5, R6, n and m are as defined above and R7 represents a amino group, for example, a compound of the formula (I) wherein R1, R2, R3, R4, R5, R6, n and m are as defined above, and R7 is a nitro group, is reduced in a known manner per se. This reduction can be carried out by catalytic hydrogenation or hydrogenation by catalytic transfer or otherwise known from the literature. c) The preparation of the compounds of the formula (I) wherein R 1 and R 2 signify an alkyl group or one of them represents hydrogen, R 3, R 4, R 5, n and m are as defined above, R 6 is an alkyl or benzyl and R7 represents an alkylsulfonamido, benzamido, alkyl (thio) ureido or aliphatic alkylcarbonylamino group (for example, acetylamino), it can be carried out, for example, by the reaction of the compounds of the formula (I), wherein R1 , R 2, R 3, R 4, R 5, R 6, n and m are as defined above, and R 7 signifies an amino group, with a suitable reagent for the introduction of a sulfonyl group, or with acylation reagents in various solvents. According to a preferred embodiment, process c) above, the compounds wherein R7 signifies an alkylsulfonamido, benzamido or alkylcarbonylamino group, are reactivated in the presence of an acid-binding agent (e.g., triethylamine). This reaction is carried out at room temperature or, if necessary, the reaction mixture is cooled or heated. According to another preferred embodiment of the compounds of process c) above, wherein R7 signifies an alkyl (thio) ureido group, they are reactivated in dioxane without any acid binding agent at room temperature or under heating. d) For the preparation of the compounds of the formula (I) wherein R 1 and R 2 represent an alkyl group or one of them is hydrogen, R 3, R 4, R 5, n and m are as defined above, R 6 represents an alkyl group and R7 represents an alkylamino group, for example a compound of the formula (I), wherein R1, R2, R3, R4, R5, R6, n and m are as defined above and R7 is an alkylcarbonylamino group, can be reduced in a way known per se.

According to a preferred embodiment of process d), this reduction is carried out using lithium aluminum hydride at the boiling point of tetrahydrofuran. e) For the preparation of compounds of the formula (I), wherein R 1 and R 2 represent an alkyl group, halogen or one of them is hydrogen, R 3, R 4, R 5, n and m are as defined above, R 6 represents a alkyl, hydrogen or benzyl group, and R7 represents a methanesulfonamido group, for example, a compound of the formula (III), wherein R1, R2, R3, R4, R5, R6, R7, n and m are as defined above, are reduced in a manner known per se. According to an advantageous embodiment of process e), this reduction is established using lithium aluminum hydride in tetrahydrofuran at the boiling point. The compounds of the formula (III) used in the process e) can be prepared, for example, by reacting the amines of the formula (II) with (methanesulfonamido) -phenylacetic acid. According to a preferred embodiment of the above process used for the preparation of the compounds of the formula (III), the reaction is carried out in N, N-dimethylformamide, in the presence of 4-methylmorpholine, isobutyl chloroformate and triethylamine in a temperature of -10 ° C and subsequently 0 ° C, or the reaction is carried out in tetrahydrofuran in the presence of dicyclohexylcarbodiimide. f) For the preparation of compounds of the formula (I), wherein R 1 and R 2 represent an alkyl group, halogen or one of them is hydrogen, R 3, R 4, R 5, R6, n and m are as defined above and R7 represents a methanesulfonamido group, for example, a compound of the formula (II) wherein R1, R2, R3, R4, R5, R6, n and m are as defined previously, they are reactivated with N- [4- (2-bromoethyl) -phenyl] sulfonamide. According to a preferred embodiment of process f), this reaction can be carried out under heating without any solvent. The salts of the compounds of the formula (I) of the present invention are formed directly in the reaction of their preparation or, when the compounds of the formula (I) are separated in their base form, the salts can be prepared from of the obtained base, by dissolving the base in a suitable solvent, such as methanol, ethanol, isopropanol, ethyl ether, ethyl acetate or in a mixture thereof, and then adding to the solution the appropriate acid dissolved in a suitable solvent. The salts can be separated directly by filtration, or by complete or partial evaporation of the solvent. Frequently, the salts of the compounds of the formula (I) according to the present invention contain the acid component in a non-stoichiometric ratio and / or they are frequently crystallized in the form of a hydrate. The present invention also relates to these crystal forms. The components of the formula (I) according to the present invention can optionally also contain asymmetric carbon atoms and therefore they can occur in optically or racemic active modifications. The optically pure compounds can also be prepared from optically pure precursors as starting materials; or the racemic end product can be resolved. In the latter case, the optical isomers can be separated, for example, by treatment of the racemic component, for example, in methanol, ethanol, ethyl acetate, acetone or other solvent with an optically active acid, for example, with an amount molar from 0.5 to 2.0 [calculated for the compound of the formula (I)] of for example, D-tartaric acid, 0.0-dibenzoyl-L-tartaric acid, 0.0-dibenzoyl-D-tartaric acid, -N , N-dimethylmonoamide, L-thiazolidine-4-carboxylic acid or other optically usual active acid, in order to obtain the diastereomer salt of an optical isomer in an immediately pure state or optionally after several recrystallizations (depending on the acid used); and the other isomer is obtained by processing the mother liquors in the base form, or in the form of a salt thereof (which depends on the amount of the acid used), which is further purified, when necessary . Then, optically active bases can be released from their salts obtained in this way and separated, if desired, to prepare an acid addition salt from the base obtained with a therapeutically acceptable acid. As mentioned above, the compounds of the formula (I), according to the present invention possess valuable antiarrhythmic effects. Next, the pharmacological results will be explained, which prove that the electrophysiological cardiac effect of class IB and III of the compounds of the formula (I) without a negative nototropic action and that induces the arrhythmia, for example, pro arrhythmia, respectively, which are characteristic of classes IB and III. Finally, the in vivo antiarrhythmic action of the compounds of the formula (I) will be shown in three arrhythmia models. Electrophysiological cellular measurements. The method used is essentially in accordance with the method of Varro and associates [Arch. Int. Pharmacodyn. Ther. 292, pages 157 to 165 (1988)]. The right ventricular trabeculae of the heart of mestizo or crossed dogs (weighing 5 to 10 kg each) were prepared. The surviving heart pieces were placed in an organ bath (37 ° C) with a content of a modified Tyrode nutrient medium and excited by spot stimulation with a baseline frequency of 1 Hz. Extracellular bipolar platinum electrodes were placed on the surface of the preparations, by means of which the propagation of surface potentials was recorded; in this way, it was possible to make the determination of the impulse conduction time or the impulse conduction rate, respectively, and the effective refractory period (ERP). During our experiments, the stimulation frequency was temporarily varied from 0.5 Hz to 3 Hz. The tested compounds were added directly to the organ bath after dilution of the material according to the desired final concentration. The effects of the compounds were observed after waiting for an incubation period of 30 to 40 minutes. The results of extracellular cardiac electrophysiological measurements in vitro are shown in Table 1.

Table 1 Effects of investigated compounds on impulse conduction and effective refractory period (REP) in the right ventricular trabeculum isolated from dog hearts.

N: Total number of animals in the group.

From the compounds investigated, the compounds of Examples 9, 15, 6, 17 and 24, significantly prolonged the time of impulse conduction in a frequency-dependent manner, for example, they decrease the amount of conduction of impulse, together with the simultaneous prolongation of the effective refractory period (REP). Mexilitin (chemically 2- (2,6-dimethyl-phenoxy) -1-methylethylamine hydrochloride), used as a reference substance, exerted an effect mainly on impulse conduction where d-sotalol showed a considerable effect only in the PRE .

Intracellular microelectrode techniques The method used is essentially in accordance with the method of Papp and associates (J. Cardiovacular Pharmacol. Ther. 1, 287-296 (1996)). The right ventricular papillary muscle and the Purkinje fibers were prepared from the hearts of crossed dogs (weighing each from 5 to 10 kg). The preparations took place in an organ bath that (37 ° C), which contains the modified Tyrode nutrient medium. The preparations were excited by a baseline frequency of 1 Hz. During the experiments, the stimulation frequency was varied according to wide limits, by means of a computer-guided stimulation. The intracellular action potentials were recorded, using glass capillary microelectrodes filled with a 3 N potassium chloride solution (standard intracellular microelectrode techniques). The remaining potential (RP), the amplitude of action potential (APA), as well as the duration of the action potential (APD), were measured using an IBM 386 compatible computer, by means of software developed for the situation. The compounds under test were added directly into the organ bath, after dilution of the storage solutions according to the desired final concentrations. The effects of the compounds were observed after an incubation time of from 30 to 40 minutes. Table 2 shows the results of intracellular cardiac electrophysiological measurements of the capillary muscle. From the compounds tested, the compounds of Examples 9, 14, 15, 16, 17, 2, 26 and 27 induced a mexiletine-like inhibition of Vma ?, which may be characterized by a relatively significant degree of rapid recovery kinetics together with simultaneous prolongation of action potential duration (APD) (effect similar to dofetilide; chemically dofetilide is N- [2- [N-methyl-N- [2- (4-methanesulfonophenoxy) ethyl] -amino] ethyl] phenyl] methanesulfonamide). In this experiment, an essential difference between the effects of the compound of Example 15 and its enantiomers (Examples 16 and 17) could not be observed.

Table 2 Effects of the compounds under test on the potential parameters RP: remaining potential; APA: amplitude of the action potential; APD: duration of the action potential; APD50: 50% repolarization time, APD90: 90% repolarization time; Vmax: maximum frequency of depolarization; Trecuperacin: constant of Vmax recovery type; Gy: rapid restoration kinetics.

The effects of the compounds tested in accordance with the present invention on the action potential of the Purkinje fibers isolated from the dog heart are totalized in the compound of Example 15 found in Tables 3 and 4.

The compound of Example 15 (5 μM) prolonged the APD in the dog's ventricular muscle and simultaneously shortened the APD on the dog Purkinje fibers at concentrations of 2 μM and 5 μM. This result is extremely important, since it can be expected that the compound does not increase, but rather decreases the lack of homogeneity of the ventricular repolarization (which is an important proarrhythmic factor).Table 3 Effect of the compound of Example 15 on the action potential in the Purkinje fibers isolated from the dog heart.

MPD: Maximum diastolic potential; APA: Amplitude of the action potential; APD50: 50% repolarization time; APDg0: 90% repolarization time, Vmax: Maximum depolarization frequency; N: Total number of animals in the group.

Table 4 Effect of the compound of Example 15 (5 μM) on the action potential in the ventricular muscle and Purkinje fibers of dog heart at a stimulation frequency of 1 Hz. * p < 0.05 N: total number of animals in the group Investigation of the effect on early post-depolarization (Figure 1 ) Early post-depolarization (EAD) was induced in the dog Purkinje fibers by the simultaneous use of 1 μM of dofetilide and 20 μM of BaCl2. These EAD-s were abolished by the addition of the compound (2 μM) of Example 15. The result of these experiments indicates that in contrast to d-sotalol, it can be expected that the compound of Example 15 does not induce a "dot-tressing". (torsade de pointes) type tachycardia, for example, a proarrhythmic complication connected with the prolongation of repolarization.

In vitro measurement of contraction force The method used is essentially in accordance with the method of Virág and associates [Gen. Pharmac. 27, pp, 551-556 (1996)]. Papillary muscles of rabbit hearts were prepared (weighing each of 2 to 3 kg.), and placed inside an organ bath at (37 ° C), which contains a modified Tyrode nutrient medium. The preparations were stimulated by point stimulation with a baseline frequency of 1 Hz. The contraction force was measured, using an auxotonic method. The compounds under test were added directly into the organ bath after dilution of the matepal solution, according to the desired final concentrations. The effects of the compounds were observed after an incubation period of 30 to 45 minutes. Using this method, the information used concerning the direct cardiac effects of the investigated compounds can be obtained. The effect of the compound of Example 15 on the contraction force is illustrated in the ventricular papillary muscle at a frequency of 1 Hz in Figure 2. The results showed that the expected therapeutic concentration of Example 15 does not induce negative inotropic action some, since the contraction force of the papillary muscle did not decrease when using a concentration lower than 30 μM.

Acute toxicity Determination of the LD5o value in mice Animal: female CDI mice (hungry), each weighing 20 to 22 kg at the time of treatment. Observation period: 2 weeks Vehicle: 1 to 2% Tween-80 in distilled water or in physiological saline, respectively. Volume of the treatment: 0.1 ml / 10 g of body weight The results are shown in Table 5. Table 5 Acute toxicity data of the tested compound of Example 15 and mexiletine, as a reference substance Investigation of arrhythmias induced by occlusion and reperfusion, following the acute ligation of the coronary artery in anesthetized rabbits. The method used is essentially in accordance with the method of Thiemermann and associates [J. Pharmacol. 97, pp. 401-408 (1989)]. A surgical loop was placed loosely around the left circumflex coronary artery of the heart, following the thoracotomy in female rabbits anesthetized with pentobarbital (30 mg / kg i.v.), (each weighing 2 to 3 kg); both ends of the coiled loop were led out of the chest through an elastic tube. The standard electrocardiogram was recorded, using needle electrodes under the skin. The blood pressure of the animals was continuously taken, using a catheter placed in the common carotid artery. After stabilization of blood pressure and heart rate, the loose loop was tightened to establish an ischemia of the regional myocardium. After 10 minutes of ischemia, the ligature was released and a reperfusion was established for 10 minutes. Survival, incidence of arrhythmias, arrhythmia access time and length of episodes were recorded. The animals received physiological (control) saline in intravenous form (2 ml / kg) or 0.03 mg / kg of the compound of Example 15 or, a dose of 3 mg / kg of d-sotalol 5 minutes before occlusion. Using this method, it was possible to show if the compound under test would be effective for the protection of arrhythmias followed by coronary artery ligation. The experiments carried out indicated (see Tables 6 and 7), that the compound of Example 15 administered in a dose of 0.03 mg / kg, has a strong antiarrhythmic effect in rabbits, compared with reperfusion arrhythmias induced by ligation.

Free Reperfusion VF VT Except Bigeminy VEB S + B + VEB Brady Death s > Control 0/6 (0%) 4/6 (67%) 4/6 (67%) 0/6 (0%) 0/6 (0%) 3/6 (50%) 3/6 (50%) 0/6 (0%) 3/6 (50%) d-Sotalol * 3/11 (27%) 2/11 (18%) 4/11 (36%) 7/11 (64%) 6/11 ( 55%) 8/11 (73%) 8/11 (73%) 0/11 (0%) 2/11 (18%) Example 15 * 3/11 (27%) 3/11 (27%) 4 / 11 (36%) 1/11 (9%) 2/11 (18%) 5/11 (45%) 6/11 (55%) 1/11 (9%) 3/11 (27%) *: 3.0 mg / kg; **: 0.03 mg / kg; Free: arrhythmia did not occur; VT: ventricular tachycardia; VF: ventricular fibrillation; EBV: sporadic ventricular strasstoles; S: saved; B: bigeminal; Brady: bradycardia Investigation of occlusion and reperfusion arrhythmias followed by acute coronary ligation in anesthetized dogs The method used is essentially in accordance with the Végh method. and associates [Basic Res. Cardiol. 82, 159-171 (1987)]. Crossed dogs of both sexes were anaesthetized, each weighing 10 to 20 kg, by means of a mixture of chloralose (60 mg / kg) and urethane (200 mg / kg), and the animals were kept on artificial respiration. After opening the chest, the ramus descendens anterior (LAD) branch of the left coronary artery of the heart was prepared from the first main collateral branch and a loose loop was placed around it from the surgical thread. During our experiments, measured the blood pressure of the animal, using a cannula introduced in the left femoral artery and in the same way the standard ECG parameters were recorded, using needle electrodes. Arrhythmias were induced by occlusion for 25 minutes, from a loop placed around the LAD. Survival was recorded after lethal arrhythmias and the frequency of arrhythmias. The compound of Example 15 was administered to 8 animals in a dose of 1 mg / kg; d-sotalol was administered to 10 animals at a dose of 3 mg / kg by intravenous injection, 10 minutes before compression of the coronary vessel. The control dogs (10 animals) received 5 ml of physiological saline in the same manner as the treated animals. Using this method, it was possible to show if the substance investigated would be effective to protect against arrhythmias followed by the ligation of the coronary artery. The experiments carried out indicated (Table 8) that a dose of 1 mg / kg of the substance of Example 15, protected from the arrhythmogenic effects of ligation and reperfusion of the coronary artery to a higher degree than a dose of 3 mg / kg of d-sotalol, an observation that proves the significant antiarrhythmic effectiveness of this compound.

Table 8 Investigation of arrhythmias due to occlusion and reperfusion, followed by acute compression in anesthetized dogs.

ES: extrasystoles; VT: ventricular tachycardia; VF: ventricular fibrillation; N: total number of animals in the group.

Arrhythmia due to occlusion followed by acute coronary artery ligation in conscious rats The method used is essentially in accordance with the method of Leprán and associates [Pharmacol. Methods 9, pp. 219-230 (1983)]. During a previous operation, the female rats, each weighing 340 to 360 g, were fitted with a loose loop of surgical thread around the left descending coronary vessel, approximately 2 mm from its origin. The ends of the loop thread were led out of the chest under the skin and then the surgical wound was closed. After completing the recovery of this previous operation / from 7 to 8 days), acute myocardial ischemia is induced, contracting the linkage in conscious animals, in free movement. The EGC was recorded continuously, using bipolar electrodes in the chest, before the ligation of the coronary artery and during the first 15 minutes of the ischemia. The survival rate was determined and the arrhythmias developed were evaluated according to the Lambeth Convention [Waiker and associates: Cardiovasc. Res. 22, pages 447-455 (1988)]. During the evaluation of the arrhythmia episodes, he also used a rating system, considering the severity of the episodes based on a rating system from 0 to 6. Both the d-sotalol and the substance of Example 15 respectively were suspended in 1% methylcellulose and administered orally through a gastric tube, one hour before compression of the coronary vessel. The control animals received a treatment with the same volume, for example 5 ml / kg of vehicle. On conscious rats, in the arrhythmia model followed by acute coronary artery occlusion, the compound of Example 15 (which has a mixed mechanism of action), showed an antiarrhythmic effect even after oral administration, while prolongation repolarization -sotalol, only proved inactive in these experiments (Table 9). Another preferred effect of the use of the compound of Example 15, is that using a dose of 25 mg / kg, the heart rate did not have statistical changes during the first 15 minutes of myocardial infarction; in contrast to the heart rate of the untreated control group, which decreased by approximately 15%.

GJ N: total number of animals in the group; n: number of animals that give an adequate response; free: no arrhythmia was observed; VF: ventricular fibrillation; VT: ventricular tachycardia; Other: ventricular extrasystoles, bigeminy, except; Brady: Bicardia. The asterisk means a statistically significant deviation: P < 0.05 The compounds according to the present invention can be used in mammals, including humans, for the elimination of cardiac arrhythmias. For therapeutic purposes, the compounds according to the present invention and the therapeutically acceptable salts thereof may be used alone or conveniently in the form of therapeutic compositions. The present invention also relates to these compositions. These therapeutic compositions contain an amount of the compound of the formula (I) or a therapeutically acceptable salt thereof, as an active ingredient, which is required to exert the effect in a mixture added with vehicles, fillers, dilution agents and / or other pharmaceutical auxiliaries commonly used in the manufacture of medicines. Suitable carriers, diluting agents or fillers may be, for example, alcohols, gelatin, lactose, sucrose, starch, pectin, magnesium stearate, stearic acid, talc, various oils of animal or vegetable origin, as well as glycols, for example propylene glycol or polyethylene glycol. Pharmaceutical auxiliaries are, for example, stabilizers, antioxidants, various natural or synthetic emulsifiers, dispersing or wetting agents, coloring agents, flavoring agents, regulators, disintegrating agents and other substances that promote the biological availability of the active agents.

The pharmaceutical compositions according to the present invention may be in the usual pharmaceutical dosage forms. Said usual dosage forms are, for example, oral compositions (administered through the oral route), prepared using pharmaceutical auxiliaries; these are solid forms, such as, for example, tablets, capsules, powders, pills, pills, dragées or granules; or liquid compositions, such as syrups, emulsions or suspensions; rectal compositions such as suppositories (which can be administered through the rectal route); and parenteral compositions (administered avoiding the gastric or intestinal system), such as injections or infusions. Although the doses of the compounds of the present invention required for the therapeutic action depend on the individual status and age of the patient and are finally determined by the physician, during the treatment of diseases accompanied by arrhythmia, they can be administered orally or parenteral daily, for example, intravenous, a dose of the compound of between approximately 0.1 mg and 5.0 mg, preferably approximately between 0.1 mg and 2.0 mg, calculated per kg of body weight. Next, in the non-limiting examples, the compounds according to the present invention and the processes for their preparation are illustrated. Example 1 N- [2- (2,6-Dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine hydrochloride To a solution containing 12.0 g (62 mmol) of N-methyl- 2- (2,6-dimethylphenoxy) -1-methylethyl amine (BE 626,725) in 40 ml of isopropanol, 7.13 g (31 mmol) of 4-nitrophene bromide are added and the reaction mixture is boiled under reflux for 5 hours. After evaporation of the solvent, the residue is triturated with 20 ml of ethyl acetate. The precipitated amine bromohydrate is filtered and washed with ethyl acetate. After evaporation of the solution, the crude product (base) obtained is purified by column chromatography (eluent: dichloromethane / methanol = 9: 0.1). The total yield (HCl salt) is 0.88 g (7.5%) of a white, crystalline product, m.p .: 135-138 ° C. 1HMR (CDCl 3, very dilute solution): 1.15 (m, 3H, C-CH 3); 2.25 (s, 6H, Ar-o-CH3); 2.90-4.20 (m, 10H, 0-CH2-CH-N, N-CH3, N-CH3-CH2-Ar); 6.85-7.10 (m, 3H, Ar); 7.48 (d, 2H) and 8.20 (d, 2H) (Ar); 13.0 (br. 1 H, NH +).

Example 2 N- [2- (2,6-Dimethylphenoxy) ethyl] -N-methyl-2- (4-nitrophenyl) ethylamine hydrochloride The titled compound is prepared as described in Example 1, except that used N-methyl-2- (2,6-dimethylphenoxyethylamine (BE 626,725), as a starting material to obtain the titled compound in a yield of 30% (HCl salt) of a white crystalline product, m.p .: 147-149 ° C. 1 HMR (DMSO-d6): 2.22 (s, 6H, Ar-CH3); 2.96 (d, 3H, N-CH3); 3.20-3.80 (m, 6H, CH2-CH2-N-CH2-CH2-Ar); 4.05-4.25 (m, 2H, 0-CH2-CH2); 6.80-7.00 (m, 3H, Ar); 7.55 (d, 2H) and 8.15 (d, 2H) (p-nitrophenyl); 11.54 (br. 1 H, NH +).

Example 3 N-Methyl-N- [2- (2-methylphenoxy) ethyl] -2- (4-nitrophenyl) -ethylamine hydrochloride The title compound is prepared as described in Example, except that the N-methyl- 2- (2-methylphenoxy) ethylamine (Example 43), is used as a starting material to obtain 28% (HCl salt) of a white crystalline product, mp: 137-138 ° C. 1 HMR (DMSO-d6) 2.12 (s, 3H, Ar-CH3); 2.95 (s, 3H, N-CH3); 3.28 (t, 2H, CH2-CH2-Ar); 3.35-3.80 (m, 4H, CH2-N-CH2); 4.42 (t, 2H, O-CH2-CH2); 6.80-7.20 (m, 4H, Ar); 7.60 (d, 2H) and 8.22 (d, 2H) (p-nitrophenyl); 1 1.25 (br. 1 H, NH +) Example 4 (S) -N- [2- (2,6-Dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenol) ethylamine The titled compound was prepared as described in Example 1, except that (S) -N-methyl-2- (2,6-dimethyphenoxy) -1-methylethylamine (Example 47) was used as the starting material to give a yield of 17% (base ) of an oily substance, which contains 1% R-enantiomer based on the HPLC chiral exam (Oral Chiralcel column); Rf = 0.7 (ethyl acetate / methanol = 9.1).

Example 5 (R) -N- [2- (2,6-D -methylphenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine The titled compound was prepared as described in Example 1, except that (R) -N-methyl-2- (2,6-dimethylphenoxy) -1-methylethylamine (Example 46) was used as the starting material to produce a (base) yield of 17%, oil that does not contain S-enantiomers at the base of the HPLC chirurgical examination (Column OJ Chiralcel) Rf = 0.7 ethyl acetate / methanol = 9.1).

Example 6"N-Methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-nitrophenyl) ethylamine hydrochloride The titled compound is prepared as described in Example 1, except that the N-methyl-2- (2-methylphenoxy) -1-methylethylamine (Example 48) is used as the starting material to obtain a yield of 14% (HCl salt) of white crystals, mp: 140-142 ° C 1HR (DMSO-af6): 1.45 (m, 3H, C-CH3), 2.10 (s) and 2.20 (s) (total 3H, Ar-CH3), 2.88 (m, 3H, N-CH3), 3.20 - 3.60 (m, 4H, N-CH2-CH2-Ar), 3.92 (m, 1 H, CH2-CH-N), 4.35 (m, 2H, O-CH2-CH), 6.80 - 7.20 (m, 4H , Ar), 7.60 (m, 2H) and 8.22 (d, 2H) (Ar); 1 1.20 (br S, 1 H, NH +).

Example 7 N- [2- (2,6-dimethylphenoxy) ethyl] -N-methyl-2- (4-aminophenyl) ethylamine A solution containing 0.40 g (1.23 mmol) of N- [2- (2,6- dimethylphenoxy) ethyl] -N-methyl-2- (4-nitrophenyl) ethylamine (Example 2) in 7 ml of isopropanol is added to a suspension of 0.1 g of 10% palladium on carbon catalyst in 7 ml of sodium propane. The suspension is hydrogenated under atmospheric pressure. After the reaction has been completed, the catalyst is filtered and washed with sodium propane. The filtrate is evaporated to a constant weight under reduced pressure to obtain 0.37 g of an oily base (76%), Rf = 0.35 (ethyl acetate / methanol = 9: 1).

Example 8 N-Ethyl-N- [2- (2-methylphenoxy) ethyl] -2- (4-aminophenyl) -etiamine The titled compound is prepared as described in Example 7, except that N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine was used as the starting material to obtain a yield of 82% of the base (oil), Rf = 0.35 (ethyl acetate / methanol = 9: 1).

EXAMPLE 9 N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine The titled compound is prepared according to the procedure described in Example 7, except that N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine (Example 1) was used as the starting material to obtain a yield of 90% of the oily base. 1 HMR (CDC13) 1 -25 (d, 3H, C-CH3); 2.32 (s, 6H, Ar-CH3); 2.48 (s, 3H, N-CH3); 2.65-2.85 (m, 4H, H-CH2-CH2-Ar); 3.28 (m, 1 H, CH2-CH-N); 3. 2 - 3.8 (br, s, 2H, NH2); 3.65 (dd, J = 9.2 and 6.7 Hz, 1 H) and 3.92 (dd, J = 9.2 and 5.7 Hz, 1 H) (O-CH2-CH); 6.66 (d, 2H, Ar); 6.9-7.10 (m, 5H, Ar).

Example 10 (S) -N- [2- (2,6-D-methylphenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine The titled compound is prepared as described in Example 7, except that (S) -N- [2- (2,26-dimethylphenoxy) -1-methylethyl] -N-methyl-2-2 (4-nitrophenyl) ethylamine was used (Example 4) as starting material to obtain a yield of 93% of a white oil (base), which contains 1 to 2% of the R- enantiomer at the base of the HPLC chirurgical examination (Column OJ Chiralcel); Rf = 0.35 (ethyl acetate / methanol = 9.1).

Example 1 1 (R) -N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine The titled compound is prepared as described in the Example 7, except that (R) -N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine (Example 5) was used as starting material to obtain an 89% yield of the oily white base, which contains 1% S- enantiomer at the base of the HPLC chirurgical examination (Column OJ Chiralcel); Rf = 0.35 (ethyl acetate / methanol = 9: 1).

Example 12 N-Methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-aminophenyl) ethylamine The titled compound is prepared as described in Example 76, except that N-methyl-N- [2- (2-methyl-phenoxy) -1-methylethyl] -2- (4-nitrophenyl) ethylamine (Example 6) was used as the starting material to obtain an 89% yield of the oily base. 1 HMR (CDC13) 1-16 (fd, 3H, C-CH3); 2.20 (s, 3H, Ar-CH3); 2.40 (s, 3H, N-CH3); 2.60-2.80 (m, 4H, N-CH2-CH2-Ar); 3.30-3.70 (br, s, 2H, NH2); 3.70 (m, 1 H, CH2-CH2-N); 3.82 (dd, 1 H) and 4.02 (dd, 1 H9 (O-CH2-CH); 6.60 (d, 2H) and 7.00 (d, 2H) (p-aminophenyl); 6.72-6.90 (m, 2H); 7.08 - 7.20 (m, 2H) (Ar).

Example 13 N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) ethyl] amino] -ethyl] phenyl] methanesulfonamide hydrochloride To a solution containing 1.44 g (4.82 mmol) of N- [2- (2,6-dimethylphenoxy) ethyl] -N-methyl-2- (4-aminophenyl) ethylamine (Example 7) in 50 ml of dichloromethane, then 0.50 g (4.95 mmol) of triethylamine and 0.63 g (5.5 mmol) of methanesulfonyl chloride in the form of drops are added to the solution cooled to 0 ° C in the same temperature. After further stirring the reaction mixture at a temperature of 0 ° C for one hour and washing with 30 ml of saturated sodium hydrogen carbonate solution, the aqueous phase is extracted twice with 20 ml of dichloromethane each time. The combined organic phase is washed twice with 30 ml of water each time, dried and evaporated to obtain a yield of 0.44 g (94%) of the oily base. The yield of the hydrochloride salt (HCl) is 0.244 g (47%) of white crystals, e.g. F. : 168 - 169 ° C. 1 HMR (DMSOD6): 2.25 (s, 6H, Ar-CH3); 2.95 (s, 6H, N-CH3 and overlap of S-CH3); 3.10 (t, 2H, CH2-CH2-Ar); 3.25-3.75 (m, 4H, CH2-N-CH2); 4.15 (t, 2H, 0-CH2-CH2); 6.85 - 7.05 (m, 3H, Ar); 7.14 (d, 2H) and 7.24 (d, 2H) (4-methanesulfonamido-phenyl); 9.75 (s, 1 H, Ar-NH-S); 11.20 (br, 1 H, NH +).

Example 14 N- [4- [2- [N-Methyl-N- [2- (2-methylphenoxy) ethyl] amino] ethyl] phenol] methanesulfonamide hydrochloride The titled compound is prepared as described in Example 13, except that N-methyl-N- [2- (2-methylphenoxy) ethyl] -2- (4-aminophenyl) ethylamine (Example 8) was used as the starting material to obtain a yield of 71% ( hydrochloride salt) of white crystals, e.g. f .: 180 -181 ° C. 1 HMR (DMSOde): 2.15 (s, 3H, Ar-CH3); 2.90 (d, 3H, N-CH3); 2.95 (s, 3H, S-CH3); M 3.10 (t, 2H, CH2-CH2-Ar); 3.25-3.80 (m, 4H, CH2-N- CH2); 4.44 (t, 2H, O-CH2-CH2); 6.80-7.00 (m, 2H, Ar) and 7.15-7.30 (m, 6H) (Ar); 9.75 (s, 1 H, Ar.NH-S); 11.20 (br, 2H, NH +).

Example 15 N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride The title product is prepared as described. described in the Example 13, except that N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-aminophen-I) ethylamine (Example 9) was used as the starting to obtain a yield of 56% (salt of HC1) of white crystals, mp : 224 - 227 ° C. 1HMR (DIVISOos at room temperature): 1.45 (m, 3H, C-CH3); 2.28 (s, 6H, Ar-o-CH3); 2.90 (m, 3H, N-CH3); 2.96 (s, 3H, S-CH3); 3.00-3.50 (m, 4H, N-CH2-CH2-Ar); 3.90 (m, 1 H, CH 2 -CH-N); 3.98-4.16 (m, 2H, 0-CH2-CH); 6.90-7.10 (m, 3H, Ar); 7.14-7.32 (m, 4H, Ar); 9.75 (s, 1 H, Ar-NH-S); 10.90 (br S, 1 H, NH +).

Example 16 (S) -N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methyl-ethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride The compound titled is prepared as described in the Example 13, except that (S) -N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine (Example 10) was used as the starting material for obtain a yield of 63% (hydrochloride salt) of white crystals, e.g. f .: 192 - 193 ° C. At the base of the HPLC chiral analysis (Column OJ Chiralcel), this product does not contain R- enantiomer. 1H R (DMSOdg at room temperature): 1.45 (m, 3H, C-CH3); 2. 28 (s, 6H, Ar-o-CH3); 2.90 (m, 3H, N-CH3); 2.96 s, 3H, S-CH3); 3.00-3.50 (m, 4H, N-CH2-CH2-Ar); 3.90 (m, 1 H, CH 2 -CH-N); 3.98-4.16 (m, 2H, O-CH2-CH); 6.90-7.10 (m, 3H, Ar); 7.14-7.32 (m, 4H, Ar); 9.70 (s, 1 H, Ar-NH-S); 1.75 (br.s, 1 H, NH +). 1 HMR (DMSOa'e, 100 ° C): 1.45 d, 3H, C-CH3); 2.28 (s, 6H, Ar-o-CH3); 2.88 (s, 3H, N-CH3): 2.96 (s, 3H, S-CH3); 2.96 (s, 3H, S-CH3); 3.00-3.50 (m, 4H, N-CH2-CH2-Ar); 3.85 (m, 1 H, CH2-CH-N); 4.04 (dd, J = 10.6 and 5.1 Hz, 1 H) and 4.14 (dd, J = 10.6 and 5.6 Hz, 1 H) (0-CH2-CH); 6.90 - 7.06 (m, 3H, Ar), 7.16 - 7.30 (m, 4H, Ar); 9.35 (s, 1 H, Ar-NH-S); 11.00 (br.s, 1 H, NH +).

Example 17 (R) -N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride The titled product is prepared as described in the Example 13, except that (R) -N- [2- (2,6-dimethylphenoxy) -1-methyethyl] -N-methyl-2- (4-aminophenyl) ethylamine (Example 11) was used as the starting material for obtain a 55% yield (HCl salt); white crystals, p. F. : 190 - 191 ° C. At the base of the HPLC chiral analysis (Column OJ Chiralcel), this product does not contain S- enantiomer. 1 HMR (DMSOc e at room temperature): 1.45 (m, 3H, C-CH3); 2.28 (s, 6H, Ar-o-CH3); 2.90 (m, 3H, N-CH3); 2.96 (s, 3H, S-CH3); 3.00-3.50 (m, 4H, N-CH2-CH2-Ar); 3.90 (m, 1 H, CH 2 -CH-N); 3.98 - 4.16 (m, 2H, O-CH2-CH); 6.90-7.10 (m, 3H, Ar); 7.14-7.32 (m, 4H, Ar); 9.70 (s, 1 H, Ar-NH-S); 10.75 (br.S, 1 H, NH +).

Example 18 N- [4- [2- [N-Methyl-N- [2- (2-methylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride The titled compound is prepared as described in he Example 13, except that N-methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-aminophenyl) ethylamine (Example 12) was used as the starting material to obtain a yield of 60% (hydrochloride salt) of white crystals, p. f .: 165 - 167 ° C. 1 HMR (DMSOd6): 1.38-1.52 (m, 3H, C-CH3); 2.10 (s) and 2.20 (s) (total 3H, Ar-CH3); 2.85 (m, 3H, N-CH3); 2.96 (s, 3H, S-CH3); 3.05-3.50 (m, 4H, N-CH2-CH2-Ar); 3.94 (m, 1 H, CH2-CH-N); 4.20-4.40 (m, 2H, O-CH2-CH); 6.80-7.00 (m, 2H) and 7.10-7.35 (m, 6H) (Ar); 9.72 (s, 1 H, Ar-NH-S); 10.70 - 1 1.00 (br. 1 H, NH +).

Example 19 N- [4- [2- [N-Methyl-N- [2- (2,3-dimethylphenoxy) -1-methylethyl] amino] etiI] phenyl] methanesulfonamide hydrochloride To a solution containing 0.82 g (2 g. mmol) of N- [2- (2,3-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) acetamide (Example 50) in 20 ml of absolute tetrahydrofuran, 0.10 was added. g of lithium aluminum hydrate (LAH) in small portions under stirring, then the mixture was boiled for about one hour in order to finish the reaction. The progress of the reaction is followed by thin layer chromatography (TLC). After completion, the excess reagent is decomposed by adding ethyl acetate, and then a 10% sodium hydroxide solution is added and then it is extracted with ethyl acetate. The combined organic phase is washed with water, and then extracted with 2N aqueous hydrochloric acid. The acid phase is alkalized to pH 9 by adding 10% sodium hydroxide and then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated under reduced pressure to obtain 0.56 g of a thick oil, as residue. This crude product is purified, if desired, by column chromatography using a mixture of hexane and ethyl acetate in a ratio of 2: 1 or 1: 1, respectively. The hydrochloride salt is obtained in a yield of 0.38 g (45%) as white amorphous flakes. 1HMR (DMSOc e): 1.40 - 1.50 (m, 3H, C-CH3); 2.00 (s), 2.08 (s) and 2.22 (s) (totally 6H, Ar-CH3); 2.80 - 2.90 (m. 3H, H-CH3), 2.95 (s, 3H, S-CH3); 3.00-3.50 (m, 4H, N-CH2-CH2-Ar); 3.92 (m, 1 H, CH2-CH-N), 4.25-4.35 (m, 2H, O-CH2-CH); 6.75-7.30 (m, 7H, Ar); 9.75 (s, 1 H, Ar-NH-S); 10.8-1.1 (m, 1 H, NH +).

Example 20 N- [4- [2- [N-Methyl-N- [2- (2,5-dimethylphenoxy) -1-methyl-ethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride The titled compound is prepared as such and as described in Example 19, except that N- (2- (2,5-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonido-phenyl) acetamide (Example 51) was used as the material starting to obtain a yield of 40% of the hydrochloride salt, which is an amorphous white precipitate HMR (DMSO / e): 1.40 - 1.50 (m, 3H, C-CH3), 2.00 (s), 2.10 ( s), 2.25 (s) and 2.26 (s) (total 6H, Ar-CH3), 2.80 - 2.90 (m, 3H, N-CH3), 2.95 (s, 3H, S-CH3), 3.00 - 3.50 (m , 4H, N-CH2-CH2-Ar), 3.92 (m, 1 H, CH2-CH-N), 4.20 -4.35 (m, 2H, 0-CH2-CH): 6.60-7.30 (m, 7H, Ar ), 9.75 (s, 1 H, Ar-NH-S), 10.65-11.00 (m, 1 H, NH +).

Example 21 Hydrogen fumarate of N- [4- [2- [N-Methyl-N- [2- (2-chlorophenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide The titled product is prepared as described in Example 19, except that N- [2- (2-chlorophenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamide-phenyl) acetamide was used as the starting material to produce a fumarate salt with a yield of 46%, mp: 152-153 ° C. 1 HMR (DMSO 6): 1.12 (d, 3H, C-CH3); 2.40 (s, 3H, N-CH3); 2.60-2.90 (m, 4H, N-CH2-CH2-Ar); 2.92 (s, 3H, s-CH3); 3.24 (m, 1 H, CH2-CH-N); 3.96 (dd, J = 10.0 and 6.0 Hz, 1 H) and 4.10 (dd, J = 10.0 and 5.6 Hz, 1 H) (0-CH2-CH); 6.60 (s, 2H, fumaric acid); 6.90-7.45 (m, 7H, Ar); 9.58 (s, 1 H, Ar-NH-S).

Example 22 N- [4- [2- [N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride A mixture of 0.58 g (2.08 mmol) of 2- (2 , 6-dimethyl-phenoxy) -1-methylethylamine (US Patent 3,659,019) and 0.3 g (1.09 mmol) of N- [4- (2-bromoethyl) phenyl] methanesulfonamide (Patent GB 971, 041) is melted at a temperature of 120 ° C for four hours. The obtained mixture is purified by column chromatography, eluted with a mixture of dichloromethane and methanol in a ratio of 9: 0.2. The product obtained is triturated with hexane and filtered to obtain the base in a yield of 64%; white crystals, p.f .: 81 - 84 ° C. 1 HMR (CDCl 3): 1.14 (d, 3H, C-CH 3); 2.18 (s, 6H, Ar-CH3); 2.86 (s, 3H, S-CH3); 2.70-3.20 (m, 5H, CH2-CH-N-CH2-CH2-Ar); 3.64 (d, 2H, O-CH2-CH); 4.0-4.6 (br., 2H, NH); 6.80-7.00 (m, 3H, Ar); 7.10 - 7.25 (m, 4H, Ar). The hydrochloride salt is obtained in a yield of 60%, in the form of white crystals, e.g. f .: 210 - 211 ° C-.

EXAMPLE 23 N- [4- [2- [N-Ethyl-N- [3- (2,6-dimethylphenoxy) propyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride The titled compound is prepared as described in Example 22, except that N-methyl-3- (2,6-dimethylphenoxy) propylamine (Patent BE 626,725) was used as the starting material to obtain the oily base in a yield of 59%. 1HMR (CDCl 3, base): 1.96 (m, 2H, CH 2 -CH 2 -CH 2); 2.26 (s, 6H, Ar-CH3); 2.35 (s, 3H, N-CH3); 2.58 -2.82 (m, 6H, CH2-CH2-N-CH2-CH2-Ar); 2.92 (s, 3H, S-CH3); 3.75 (t, 2H, 0-CH2-CH2); 6.00-6.60 (1 H, NH); 6.82 -7.02 (m, 3H, 2,6-dimethylphenoxy group); 7.16 (s, 4H, 4-methanesulfonamido-phenyl group). The hydrochloride salt is obtained in a yield of 49%; in the form of white crystals; p.f .: 1 15 - 117 ° C.

Example 24 N- [4- [2- [N-Methyl-N- [4- (2,6-dimethylphenoxy) butyl] -amino] etiI] phenyl] methanesulfonamide hydrochloride The titled compound is prepared as described in Example 22, except that N-methyl-4- (2,6-dimethylphenoxy) butylamine (Patent BE 626,725) was used as starting material to obtain an oily base in 57% yield. 1HMR (CDCl 3, base): 1.62-1.88 (m, 4H, CH2.CH2, CH2-CH2); 2.26 (s, 6H, Ar-CHs), 2.32 (s, 3H, N-CH3); 2.45-2.85 (m, 6H, CH2-CH2-N-CH2, CH2-Ar); 2.95 (s, 3H, S-CH3); 3.75 (t, 2H, 0-CH2-CH2); 5.30-6.30 (1 H, NH); 6.82-7.02 (m, 3H, 2,6-dimethylphenoxy group) 7.16 (s, 4H, 4-methanesulfonamido-phenyl group). The hydrochloride salt is obtained in a yield of 41.0%; in the form of strongly hygroscopic discolored crystals.

Example 25 N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -aminojetylj-phenyl-benzamide hydrochloride To a solution containing 0.2 g (0.64 mmol) of N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine (Example 9) in 1.7 ml of acetonitrile was added 0.11 ml. (0.768 mmol) of triethylamine, and then 0.082 ml (7.04 mmol) of benzoyl chloride was added under stirring. The reaction mixture was stirred at room temperature (cooled or heated, if necessary). After the reaction was completed, the reaction mixture was evaporated under reduced pressure, 10 ml of water was added to the evaporation residue, and the pH value was adjusted to the alkaline, if necessary, by adding a sodium hydroxide solution. The product was extracted three times with 20 ml of ethyl acetate each time. The organic phase was washed with 50 ml of water, dried and evaporated to obtain 0.24 g (90%) of an oil. 1HMR (CDCl 3): 1.16 (d, 3H, C-CH 3), 2.25 (s, 6H, Ar-CH 3); 2.45 (s, 3H, N-CH3), 2.65-2.85 (m, 4H, N-CH2-CH2-Ar); 3.26 (sx, 1 H, CH2-CH-N); 3.64 (dd, J = 9.5 and 6.1 Hz) and 3.84 (dd, J = 9.5 and 5.6 Hz, 1 H), (0-CH2-CH); 6.80-7.00 (m, 3H, Ar); 7.10 (d, 2H) and 7.80 (d, 2H) (p-benzoylamino-phenyl group); 7.25-7.45 (m, 3H) and 7.56 (d, 2H) (benzoyl group); 8.70 (s, 1 H, NH). The hydrochloride salt is obtained in a yield of 0.19 g (66%); in the form of white crystals, p. f .: 108 -1 11 ° C.

EXAMPLE 26 N- [4- [2- [N-Methyl-N- [2- (2,6-dimethyl-lphenoxy) -1-methylethyl] amino] ethyl] pheni] sesquichlorohydrate monohydrate] acetamide The titled compound is prepared as described in Example 25, except that acetyl chloride was used as the acylation reagent to produce the salt in 68% yield, in the form of white crystals, m.p .; 104 - 106 ° C. Analysis for C22H3oN2? 2 * 1.5.HCl? 20 (molecular weight 427.20); calculated: C 61.85; H 7.90; N 6.56; Cl 12.44; H20 4.22% found: C 61.79; H 7.74; N 6.34; Cl 13.96; H20 4.70% HMR (DMSOa'e): 1.40-1.50 (m, 3H, C-CH3); 2.05 (s, 3H, Ac); 2.15 (s, 6H, Ar-CH3); 2.80-2.90 (m, 3H, N-CH3); 2.90-3.60 (m, 4H, H-CH2-CH2-Ar); 3.85 (m, 1 H, CH2-CH-N); 4.05-4.15 (m, 2H, 0-CH2-CH); 6.80-7.05 (m, 3H, Ar); 7.15 - 7.25 (m, 2H) and 7.55 - 7.65 (m, 2H) (p-acetamino-phenyl); 10 ^ 15 (s, 1 H, Ar-NH-CO); 1.22 (br, 1 H, NH +).

Example 27 1-Methyl-3- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] thiourea sesquichlorhydrate sesquichlorhydrate To a solution with a content of 0.30 g (0.96 mmol) of N- [2- (2,6-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) elylamine (Example 9) in 2.5 ml of dioxane, 0.077 g (1.05 mmol) of methyl isothiocyanate was added. The reaction mixture is stirred at room temperature (and, if necessary, heated or additional methyl isothiocyanate is added). After finishing the reaction, the solvent is evaporated under reduced pressure. The evaporation residue is purified by means of column chromatography or crushed with a small amount of n-hexane, it is poured, and 10 ml of water are added to the oil, the pH value is adjusted to alkaline by adding hydroxide solution. sodium (when necessary), then the product is extracted three times with 20 ml of ethyl acetate each time. The combined organic phase is washed with 50 ml of water, dried and evaporated to obtain 0.18 g (48%) of the oily base. 1 HMR (CDCl 3): 1.06 (d, 3H, C-CH 3); 2.26 (s, 6H, Ar-CH3); 2.42 (s, 3H, N-CH3); 2.65-2.90 (m, 4H, C-CH2-CH2-Ar); 3.10 (d, 3H, NH-CH3); 3.25 (m, 1 H, CH2-CH-N); 3.62 (dd, J = 9.3 and 6.1 Hz, 1 H); and 3.85 (dd, J = 9.3 and 5.9 Hz, 1 H) (O-CH2-CH); 6.04 (d, CS-NH-CH3); 6.85 - 7.00 (m, 3H, Ar); 7. 12 (d, 2H) and 7.26 (d, 2H), (p-thioureido-phenyl group), 8.00 (s, 1 H, Ar-NH-CS). The salt is obtained in a yield of 0.136 g (31%), in the form of hygroscopic white crystals, m.p .: 120-122 ° C. Analysis for: C22H3? N3OS'1.5HCI »0.5H2O (molecular weight 449.27); calculated: C 58.82; H 7.52; N 9.35%; • found: C 58.87; H 7.61; N 8.66%.

Example 28 1-Ethyl-3- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] urea The titled compound is prepared as such and as described in the Example 27, except that ethyl isocyanate was used as reagent to obtain the oily base in a yield of 59%. 1 HMR (CDCl 3): 1.05 (t, 3H, CH 2 -CH 3); 1.15 (d, 3H, CH-CH3); 2.28 (s, 6H, Ar-CH3); 2.40 (s, 3H, N-CH3); 2.60-2.80 (m, 4H, N-CH2-CH2-Ar); 3.08 - 3.28 (m, 3H, N-CH2-CH3 and CH2-CH-N); 3.58 (dd, J = 9.1 and 6.5 Hz, 1 H) and 3.86 (dd, J = 9.1 and 5.8 Hz, 1 H) (O-CH2-CH); 6.00 (t, 1 H, CO-NH-CH2); 6.82 - 7.02 (m, 3H, o-dimethylphenoxy group); 7.05 (d, 2H) and 7.22 (d, 2H) (p-ethylureido-phenyl group); 7.90 (s, 1 H, Ar-NH-CO).

Example 29 N- [2- (2,6-Dimethylphenoxy) -1-methylethyl] -N-methyl-2- [4- (N'-ethylamino) phenyl] ethylamine The titled compound is prepared as described in Example 19, except that N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methyl-etI) amino] phenyl] acetamide was used (Example 26) as starting material to obtain the oily base in a yield of 60%. 1HMR (CDC13, base): 1.17 (d, 3H, CH-CH3); 1.21 (t, 3H, CH2-CH3); 2.30 (s, 6H, Ar-CH3); 2.42 (s, 3H, N-CH3); 2.60-2.80 (m, 4H, N-CH2-CH2-Ar); 3.11 (q, 2H, N-CH2-CH3); 3.01 (m, 1 H, CH2-CH-N); 3.59 (dd, J = 9.1 and 6.7 Hz, 1 H) and 3.86 (dd, J = 9.1 and 5.6 Hz, 1 H) (0-CH2-CH); 6.54 (d, 2H) and 7.01 (d, 2H) (p-ethylamino-phenyl group); 6.86 - 7.06 (m, 3H, o-dimethylphenoxy group).

Example 30 N- [4- [2- [N-Propyl-N- [2- (2,6-dimethylphenoxy) ethyl] amino] etl] phenyl] methanesulfonamide The titled compound is prepared as described at Example 22, except that N- [2- (2,6-dimethylphenoxy) ethyl] propylamine was used as starting material to obtain the oily base in a 25% yield. 1HMR (CDCl 3, base): 0.86 (t, 3H, N-CH 2 -CH 2 -CH 3); 1.52 (m, 2H, N-CH2-CH2-CH3); 2.27 (s, 6H, Ar-CH3); 2.60 (t, 2H, H-CH2-CH2-CH3); 2.70-2.90 (n, 4H, N-CH2-CH2-Ar); 2.95 (s, 3H, S-CH3); 2.99 (t, 2H, 0-CH2-CH2-N); 3.85 (t, 2H, O-CH2-CH2-N); 6.85-7.05 (m, 3H, 2,6-dimethylphenoxy group); 7. 16 (s, 4H, p-methanesulfonamido-phenyl group).

Example 31 N- [4- [2- [N-Methyl-N- [2- (2-isopropylamphoxy) -1-methylethyl] -amino] eti] phenyl] methanesulfonamide hydrochloride The titled compound was prepared as described in Example 22, except that N-methyl-2- (2-isopropylphenoxy) -1-methylethylamine (Example 49) was used as the starting material to obtain the oily base in a 52% yield. 1HMR (CDC13, base): 1.12-1.22 (m, 9H, CH-CH3 and Ar-CH- (CH3) 2); 2.41 (s, 3H, N-CH3); 2.70-2.80 (m, 4H, N-CH2-CH2-Ar); 3.15-3.40 (m, 2H, CH2- CH-N and Ar-CH- (CH3) 2); 3.81 (dd, J = 9.3 and 6.4 Hz, 1 H) and 4.00 (dd, J = 9.3 and 5.4 Hz, 1 H) (0-CH2-CH); 6.77 (dd, J = 8.0 and 1.0 Hz, 1 H); 6.92 (td, J = 7.5 and 1.0 Hz, 1 H); 7.10 - 7.25 (m, 6H) (Ar). The hydrochloride salt is obtained in a total yield of 38%, in the form of white crystals, m.p .: 86-89 ° C.

Preparation of the starting materials Example 32 4- (Methanesulfonamido) phenylacetic acid In a solution with a content of 5.44 g (53 mmol) of sodium carbonate in 36 ml of water, 3.2 g (20 mmol) of 4-acid were dissolved. aminophenylacetic, 1.7 ml (2.48 g, 22 mmol) of methanesulfonyl chloride was added in one portion and the mixture was heated to a temperature of 85 ° C for 4 hours. After cooling and acidifying the reaction mixture with concentrated hydrochloric acid to pH 3, the mixture was cooled in the refrigerator overnight, filtered, washed with water and dried to obtain 2.8 g of a crude product, which was returned to crystallize from 6 ml of hot water to yield 2.40 g of the titled substance in the form of beige laminar crystals; yield: 53%, p.f .: 145 - 147 ° C. HMR (DMSOd6) 2.95 (s, 3H, S-CH3); 3.48 (s, 2H, Ar-CH2-CO); 7.10 (d, 2H) and 7.18 (d, 2H) (Ar); 9.65 (br, 1 H, NH); 12.25 (Br, 1 H, COOH).

Preparation of the components of the formula (V) Example 33 1- (2,5-dimethylphenoxy) -2-propanol To a solution with a content of 3.67 g (30 mmol) of 2, 5-dimethylphenol in 16 ml of 96% ethanol, 2.61 g (45 mmol) of propylene oxide and 0.44 g (3.2 mmol) of potassium carbonate were added, then the suspension formed was boiled while stirring for 6 hours . After filtration of the reaction mixture and washing with ethanol, the solvent was evaporated under reduced pressure. The crude product (obtained in a 100% yield) was purified by distillation under reduced pressure, when necessary. The yield is 85% of a colorless liquid; boiling point 104 -107 ° C / 0.26 kPa; Rf = 0.1 (toluene).

Example 34 (R) -1- (2,6-Dimethylphenoxy) -2-propanol The titled compound is prepared as described in Example 33, except that 2,6-dimethylphenol and R (+) propylene oxide were used as starting materials to obtain the crude product in a 100% yield. Based on the HPLC chiral analysis (Column OJ Chiralcel), this product has a chemical purity of 74.4%, without S- enantiomer content.

Example 35 (S) -1- (2,6-Dimethylphenoxy) -2-propanol The titled compound was prepared as described in Example 33, except that 2,6-dimethylphenol and S (-) propylene oxide were used. as starting materials to obtain a raw product in a 100% yield. Based on the HPLC chiral analysis (Column OJ Chiralcel), this product has a chemical purity of 78%, without R- enantiomer content.

Example 36 1- (2-lsopropylphenoxy) -2-propanol The titled compound was prepared as described in Example 33, except that 2-isopropylene glycol and propylene oxide were used as starting materials to obtain the crude product in a 100% yield; Rf = 0.1 (toluene).

. Preparation of compounds of the formula (IV) General method: To a solution containing 30 mmol of the compound of the formula (V) in 10 ml of pyridine, 7.63 g (40 mmol) of 4-toluenesuiphenyl chloride were added. at room temperature while stirring. After stirring for 3 hours, the reaction mixture was poured into 55 ml of water. The product was extracted twice with 40 ml of ethyl acetate each time, the organic phase was washed twice with 25 ml of 2 N hydrochloric acid, twice with water each, twice with 20 ml of 1 N solution of Sodium carbonate each and finally three times with 20 ml of water each, and after evaporation of the solvent, if necessary, the residue of the evaporation was crystallized from a mixture of hexane and diisopropyl ether. Using the above general method, the following compounds of formula (IV) were obtained, wherein R1, R2 and R3 are as indicated in Table 10, n and m are 0 and X means a 4-toluenesulfonyloxy group, when prepared.

I heard CD a: Article by S Honma and associates, published in Chem. Pharm. Bull. 25, pages 1843 to 1850 (1977) b: Patent FR 1,386,347 Preparation of compounds of the formula (II) General Method: After reactivating 30 mmol of compounds of the formula (IV) suitably substituted (wherein X means a halogen or 4-toluenesulfonyloxy group) with 60 ml of 33% ethanolic methylamine or amine substituted at a temperature of 100 ° C in a closed tube for 5 hours, the reaction mixture was evaporated. The obtained oil is collected in 40 ml of 2 N of sodium hydrochloric acid, then the mixture is extracted three times with 50 ml of dichloromethane each time. The organic phase was washed twice with 40 ml of water each time, dried, filtered and then the solution was evaporated. The oil obtained was transformed into a salt or purified by distillation under reduced pressure or was used later in the raw form. The following compounds of the formula (II), wherein R1, R2, R3 and R6 are as defined in Table 11, and n and m are O, were prepared following the above general method. on ex »a: Beilstein 6,352; b: Patent DE 2,524,363 *: 46. aD20 = -5.0 ° C (C = 1, methanol); ** 47 aD20 = + 4.0 ° C (c = 1, methanol) Preparation of compounds of the formula (III) Example 50 N- [2- (2,3-D-methylphenoxy) -1-methylethylj-N-methyl 2- (4-methanesulfonamido-phenyl) -acetamide To a solution containing content of 0.80 g (3.5 mmol) of 4-melanosuifonamide-phenylacetic acid (Example 32) in 20 ml of N-N-dimethylformamide (DMF) 0.46 ml (0.42 g, 4.2 mmol) of methylmorpholine was added, the mixture is cooled to. a temperature of -10 ° C and 0.65 ml (0.70 g, 5 mmol) of chloroformate is added. After 10 minutes, a solution with a content of 0.68 g (3.5 mmol) of N-methyl-2- (2,3-dimethylphenoxy) -1-methylethylamine is added.

(Example 44) in 3 ml DMF previously cooled to a temperature of -10 ° C, then the pH value is adjusted to 8.5 by the addition of triethylamine. The reaction mixture is stirred at a temperature of -10 ° C for 1 hour, then at 0 ° C for 1 hour. After,. The solvent is evaporated under reduced pressure and the solid residue is made alkaline by the addition of aqueous ammonia solution and distributed between water and ethyl acetate. The aqueous phase is washed twice with ethyl acetate, the combined organic phase is washed once with water, dried over sodium sulphate and evaporated. In this way, they were obtained 1. 13 g of the substance titled as an amorphous substance, which is suitable for the next step without further purification. Performance: 80%. 1 HMR (CDCl 3): 1.18-1.38 (m, 3H, C-CH 3); 2.10 - 2.20 (m, 3H) and 2. 25-2.35 (m, 3H) (Ar-CH3), 2.85-3.05 (m, 6H, N-CH3 and S.CH3); 3.72 - 4.05 (m, 4H, 0-CH2-CH and CO-CH2-Ar); 4.45 (m) and 5.15 (m) (total 1 H, CH2-CH-N); 6.70 (dd, 1 H), 6.83 (t, 1 H) and 7.05 (dd, 1 H) (2,3-dimethylphenoxy group); 7.10 - 7.22 (m, 4H, 4-methanesulfonamido-phenyl group); 7.50 (s, 1 H, Ar-NH-s).

Example 51 N- [2- (2,5-Dimethylphenoxy) -1-methylethylj-N-methyl-2- (4-methanesulfonamido-phenyl) -acetamide To a solution with a content of 0.52 g / 2.7 mmol) of N- methyl-2- (2,5-dimethyphenoxy) -1-methylethylamine (Example 45) in 15 ml of tetrahydrofuran 0.63 g (2.7 mmol) of 4-methanesulfonamido-phenylacetic acid (Example 32) and 0.63 g ( 3.05 mmol) of dicyclohexylcarbodiimide and the reaction mixture is stirred at room temperature for 16 hours. After filtration of the mixture, the filtrate is evaporated under reduced pressure and the pale yellowish resin of about 4.5 g obtained is purified by column chromatography using a mixture of ethyl acetate and hexane as eluent. In this way, 0.76 g (70%) of the title compound was obtained as an amorphous material. 1 HMR (CDCl 3): 1.08-1.36 (m, 3H, C-CH 3); 2.10-2.18 (m, 3H) and 2.25-2.35 (m, 3H) (Ar-CH3); 2.84-3.04 (m, 6H, N-CH3 and S-CH3); 3.66 (s) and 3.80 (s) (total 2H, Co-CH2-Ar); 3.85-4.05 (m, 2H, 0-CH2-CH); 4.44 (m) and 5.10 (m) (total 1 H, CH2-CH-N); 6.56-6.62 (m, 1 H), 6.62-6.74 (m, 1 H); and 6.96 - 7.04 (m, 1 H) (2,5-dimethylphenoxy group); 7.05-7.20 (m, 4H, p-methanesulfonamido-phenyl group); 7.50-7.80 (m, 1 H, Ar-NH-s).

Example 52 N- [2- (2-Chlorophenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamido-phenyl) acetamide The titled compound is prepared as described in Example 50, except that used N-methyl-2- (2-chlorophenoxy) -1-methylethylamine (Patent FR M 5,912) as a starting material to obtain a 68% yield as an amorphous material. 1 HMR (CDCl 3): 1.25-1.40 (m, 3H, C-CH 3); 2.90 - 3.00 (m) and 3.12 (s) (total 6H, N-CH3 and S. CH3); 3.70 (s) and 3.85-4.20 (m, total 4H, 0-CH2-CH and CO-CH2-Ar); 4.52 (m) and 5.08 (m) (total 1 H, CH2-CH-N); 6.85-7.40 (m, 8H, Ar); 7.45-7.60 (m, 1 H, Ar-NH-S).

Claims (6)

R E I V I N D I C A I N N E S Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property.

1. Compounds of the formula (I) wherein R 1 and R 2, independently of one another, mean a hydrogen, halogen or Ci Ci alkyl group; R3, R4 and R5 represent, independently of one another, a hydrogen or C- alkyl group; R6 represents a hydrogen group, C-O alkyl benzyl; R 7 is a nitro group or amino group optionally monosubstituted by a C 1-4 alkyl, benzoyl, C 1-4 alkylcarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkylcarbamoyl or C 1-4 alkylthiocarbamoyl group; both of n and m are 0 or 1; with the proviso that R2 is different from hydrogen, when R1 is hydrogen; as well as the stereoisomers or mixtures of stereoisomers thereof, acid addition salts thereof and hydrates, prodrugs and metabolites of all these compounds.

2. A compound as described in Claim 1, further characterized in that it is selected from the group consisting of: N- [4- [2- [M-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl ] -amino] ethyl] phenyl] methanesuifonamide, (S) -N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy-1-methyl-etl] ami] nojetyl] phenyl] methanesulfonamide, (R) -N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] etjlphenyl] methanesulfonamide, N- [4- [2- [N-methyl-N- [2- (2-methylphenoxy) ethyl] amino] etiI] phenyl] methanesulfonamide, N- [4- [2- [N-methyl-N- [2- ( 2,6-dimethylphenoxy) -1-methylethyl] amino] etl] phenyl] acetamide, N- [4- [2- [N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide, 1-Methyl-3- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenylphiourea, 2- [4 -Aminophenyl] -N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylene] ethylene and the acid addition salts of these compounds.

3. A pharmaceutical composition, which comprises as active ingredient a compound of Formula (I), wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, n and m are as described in Claim 1, or a salt or therapeutically acceptable hydrate thereof in a mixture with solvents, diluting agents, vehicles and additives commonly used in the preparation of medicaments.

4. The compounds as described in Claim 1, further characterized in that they are for use as medicaments.

5. The use of the compounds as described in Claim 1, further characterized in that they are for the preparation of a medicament suitable for curing cardiac arrhythmia.

6. A method for the treatment of diseases accompanied by arrhythmia in mammals, which comprises administration to a mammal in need of such treatment in antiarrhythmic quantities of a compound as described in Claim 1.