CZ20002112A3 - Anti-arrhythmic compounds - Google Patents

Abstract

The present invention relates to phenoxyalkylamino derivatives of the general formula I, in which Re1 and Re2 represent independently on each another a hydrogen atom, a halogen atom or an alkyl group containing 1 to 4 carbon atoms; Re3, Re4 and Re5 denote independently on each other a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; Re6 represents a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms or a benzyl group; Re7 denotes a nitro group or an amino group, being optionally monosubstituted with alkyl group having 1 to 4 carbon atoms, a benzoyl group, an alkylcarbonyl group containing 1 to 4 carbon atoms, an alkylsulfonyl group containing 1 to 4 carbon atoms, an alkylcarbamoyl group containing 1 to 4 carbon atoms or an alkylthiocarbamoyl group having 1 to 4 carbon atoms; both the n and m are 0 or 1; with the proviso, that Re2 differs from the hydrogen atom provided Re1 is a hydrogen atom, and their stereoisomers or stereoisomer mixtures, acid addition salts and hydrates, precursors and metabolites of all the above-indicated compounds. Disclosed are also pharmaceutical compositions containing the above-described compounds wherein these compounds exhibit a valuable antiarrhythmic activity.

Description

Technical field

The invention relates to novel antiarrhythmic active phenoxyalkylamine derivatives having a dual effect. In particular, the invention relates to novel phenoxyalkylamine derivatives of the general formula I

R '

R *

W \ // ~ ^o “ ^CH 2 ^CH - <9 ^H > to ^CH feN- (CH ₂ )

(I) to \ //

R, and salts thereof, as well as pharmaceutical compositions containing these compounds.

BACKGROUND OF THE INVENTION

Cardiac arrhythmias are known to be one of the most serious cardiovascular disorders. The most serious of these is ventricular heart fibrillation, the most common cause of sudden cardiac failure, and in the US alone, it leads to approximately 400,000 deaths each year. Serious complications also accompany atrial fibrillation, which occurs in nearly one million people.

The most widespread treatment method is medication. However, the drugs currently available cannot be considered the best solution, by virtue of their serious side effects, which substantially limit their use. From this

01-1644-00-Ma negative results of two series of publicly available clinical examinations [CAST I and CAST II; CAST Investigators, N. Engl. J. Med. 321, 406 (1989) and ibid. 327, 227 (1992)] show that some antiarrhythmic agents, the so-called IC classes with slow regeneration kinetics, which inhibit the maximum rate of repolarization of the heart action potential, the sodium channel, reduce the chances of patients recovering. from heart attack to survival [current classification of antiarrhythmic drugs can be found in AO Grandt, Jr., for example. and N.C. Durham: Am. Heart J. 123: 1130 (1992)]. These undesirable results can be associated with proarrhythmic (i.e. arrhythmia and negative inotropic (i.e.

cardiac output) by the action of class IC antiarrhythmic agents. Later, it has been shown that, like these agents, Class III antiarrhythmic agents, which were given increased attention in the early 1990s [which extend the duration of the action potential and thus the effective refractive period (abbreviated ERP)], are not devoid of dangerous side effects; and clinical trials performed with d-sotalol (chemical designation dN [4- [1-hydroxy-2- (1-methylethylamino) ethyl] phenyl] methanesulfonamide hydrochloride) as a class III prototype were discontinued in the treated group due to increasing mortality, attributable to a proarrhythmic effect [see, for example, P. Matyus, A. Varro, J. Gy. Papp et al., Med. Res. Roar. 17, 427 (1997)]. The use of two additional classes of antiarrhythmic agents (II and IV) as well as two other subgroups (IA and IB) of Class I sodium channel blocking agents is associated with serious hazards or limitations (especially in the case of Class IV and IA antiarrhythmic agents).

It follows from the above that there is currently a high demand for a new type of safe but at the same time

01-1644-00-Ma of a sufficiently effective antiarrhythmic agent. It is an object of the present invention to provide an active ingredient, e.g. a composition that would meet these requirements.

A variety of phenoxyalkylamine derivatives are known in the literature. However, these derivatives differ both in their chemical structure and biological activity from the compounds of formula I according to the invention.

The following is a summary of only those references that describe / those whose structure closest to that of the compounds of the invention.

EP 245,997 relates to antiarrhythmic active bis (aralkyl) amines and phenoxyalkylamine derivatives, some of which also have a positive inotropic effect. According to the authors, these compounds are selective class III antiarrhythmic agents. The derivative of the general formula VI ch ₃ so ₂ nh has proved to be the most effective

ch ₃ o— (CH ₂ ) ₂ -N - (CH ₂ )

nhso ₂ ch ₃ (VI) containing a methanesulfonamide group at the 4-position of both phenyl rings.

Japanese Patent Application Publication No. 06,107,614 discloses compounds that are not within the scope of the invention and which may be characterized by Formula I wherein R ¹ , R ^2, and R ³ are hydrogen; both n and m are 0 or one is 1; R ⁶ represents a hydrogen atom, an alkyl group, a formyl group or an alkylthiocarbamoyl group; and R ⁷ is an amino group substituted with p-chlorobenzenesulfonyl, 2,4,6-triisopropyl01-1644-00-Ma

• 9 · 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 benzenesulfonyl, 8-quinolinesulfonyl, 1-naphthoyl or 2-pyridinecarbonyl. Anti-ulcer effects appear from the description of these compounds.

U.S. Patent No. 4,044,150 discloses the 4 '- [1-hydroxy-2 - [(1-phenoxyethyl) amino] ethyl] methanesulfonanilide of Formula VII

OH

O- (CH ₂ ) ₂ -NH-CH ₂ -CH ₂ -CH ₂ -NHSO ₂ CH ₃ (VII) and its salts, which have a chemical structure very similar to that of the compounds of the invention. According to the present inventors, these agents are as β-adrenergic receptor blocking agents and as agents that can be used as antihypertensive agents.

Phenoxyalkylamine derivatives having chemical structures similar to those of the compounds of the invention in which a phenoxy group may be monosubstituted or disubstituted by a hydrogen, halogen, hydroxyl or alkoxy group, while the phenyl group (s) at the other end of the alkylaminoalkyl chain may be disubstituted or trisubstituted para-hydroxyl or amino and / or metahalogen (halogens) as well as trifluoromethyl, cyano or nitro (groups) are also known from patent application GB 2,088,873. According to the authors, these compounds act on the heart and blood circulation, and more specifically exhibit antihypertensive, antiarrhythmic and / or cardiotonic effects. However, the biological data reported in the description only confirm the positive inotropic activity of these compounds.

01-1644-00-Ma

Interestingly, compounds analogous to the compounds of formula I of the present invention wherein the phenoxy group is substituted with an acylamino group and the phenyl group at the other end of the alkylaminoalkyl chain is substituted with a C 1 -C 4 alkyl group or an alkoxy group and / or a hydrogen atom ( thus, they contain a substitution inversion for the compounds of the invention), exhibit antitumor effects (EP 494,623).

It has surprisingly been found during the tests that the compounds of the formula I exhibit a strong antiarrhythmic effect and have no undesirable side effects. The combined mechanism of action of these agents yields more beneficial results in terms of antiarrhythmic effect and extends to a wider spectrum than the effect of individual IB and III components. At the same time, it has been shown that the compounds of the formula I according to the invention do not show the serious adverse effects which are characteristic of the compounds of classes I and III.

These favorable general formula I pharmacological properties of the compounds are of great surprise in view of the data reported in the literature. In particular, as regards the chemical structure requirements of Class IB and III antiarrhythmic drugs, it is suggested that Class IB antiarrhythmic activity is characteristic of ortho-disubstituted phenoxyalkylamino (or isosteric) systems containing a short alkyl chain and an amino substituent with low steric requirements (eg tocainide, lidocaine) ); whereas compounds exhibiting a potent class III activity are characterized by a structure comprising two phenyl groups linked together by a relatively long chain in which both phenyl groups are arranged in para-position, i.e. they represent symmetrically situated substituents providing electrons [more detailed analysis of structure-activity dependencies

01-1644-00-Ma find eg in: P. Mátyus, A. Varro, J. Gy . Papp et al., Med. Res. Roar. 17, 427 (1997)].

Thus, it is surprising to those skilled in the art that the compounds of formula I of the invention, which are structurally quite different from typical representatives of both class IB and class III antiarrhythmic agents, exhibit a significant antiarrhythmic effect associated with both type IB and III effects while being free proarrhythmic or negative inotropic effects.

It is known in the literature that dual-action compounds are very important for pharmaceutical chemistry [see, for example: "The Practice of Medicinal Chemistry, pp. 216-293, Ed. C.G. Wermuth, Academic Press, London (1996)]. In this case, the combination of the two aforementioned antiarrhythmic mechanisms of action is even more advantageous than the conventional mechanism, since it provides qualitatively new, extremely favorable properties; in particular, due to the simultaneous presence of the two components of action, the compounds of the formula I do not show proarrhythmic or negative inotropic effects. On the other hand, this combination of effects provided by one and the same molecule, in terms of pharmacokinesis as well as drug safety, is more advantageous than the combination of both individual molecules.

Taking into account also the low toxicity of the compounds of the formula I, these compounds can be considered as safe antiarrhythmic agents of a new type with a broad spectrum of activity.

01-1644-00-Ma ............

• · 9 · <·· <♦ ♦ • · ♦ · 9 · 9 9 9 9

9 9 9 9 9 · 9 9 9 9 9 9 9

9 9 · 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

SUMMARY OF THE INVENTION

The invention therefore relates to compounds of formula I

in which

R ¹ and R ² independently represent hydrogen, halogen or C 1 -C 4 alkyl;

R ³ , R ⁴ and R ^{5 are} independently hydrogen or C 1 -C 4 alkyl;

R ⁶ represents a hydrogen atom, a C 1 -C 4 alkyl group or a benzyl group;

R ⁷ is nitro or amino, optionally monosubstituted C 1 -C 4 alkyl, benzoyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylcarbamoyl, or alkylthiocarbamoyl C 1 -C 4;

both n and m are 0 or 1;

with the proviso that R ² is other than a hydrogen atom when R ¹ is a hydrogen atom, and stereoisomers or mixtures of stereoisomers, acid addition salts and hydrates, precursors, and metabolites thereof.

01-1644-00-Ma

4

4

4 44

44 · ♦ 4 44444 · 4 4444 44 44 «444

44 43 · 4 4 «44

For compounds of the invention, the alkyl groups may have a straight or branched carbon chain; and the halogen may be bromine, chlorine or fluorine.

It follows from the above that R ¹ and R ² can independently be methyl, ethyl, n-propyl, isopropyl or butyl in formula I, and also fluorine, chlorine or bromine. In the case where one of R ¹ and R ² represents a hydrogen atom, the other substituent should have a different meaning. Thus, for example, the substituted phenoxy group of formula (I) may be 2,3-dimethylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy, 2,6-dimethylphenoxy, 2,6-diethylphenoxy, 2-ethyl-6-methylphenoxy, 2-chloro- 6-methylphenoxy, 2,6-dichlorophenoxy, 2-bromo-6-methylphenoxy, 2,6-dibromophenoxy, 2-bromo-4-chlorophenoxy, 2-methylphenoxy, 2-ethylphenoxy, 2-isopropylphenoxy, 2-chloro, 2-chlorophenoxy, bromophenoxy or 2-fluorophenoxy.

R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a butyl group; and then R ⁶ may also represent a benzyl group; and R ⁷ may be, for example nitro, amino, methylamino, ethylamino, propylamino, butylamino, acetylamino, propionylamino, isopropionylaminoskupinu, butanoylaminoskupinu, benzoylamino, methansulfonamidoskupinu, ethansulfonamidoskupinu, n propansulfonamidoskupinu, isopropylsulfonamidoskupinu, butansulfonamidoskupinu, methylureido, ethylureidoskupinu, n-propylureido, isopropylureido, methylthioureido or ethylthioureido.

01-1644-00-Ma

Φ φ * * * * * * φ φ φ φ φ φ · · · · · · ·

A preferred group of compounds of formula (I) according to the invention is that represented by compounds wherein R ¹ is an alkyl group, R ² to R ⁷ and ⁿ are as defined above and m is 0.

Another preferred group of compounds of the invention are those compounds of formula I wherein both R ¹ and R ² are 2,6-dialkyl, R ³ and / or R ⁶ are alkyl, R ^{7 and} n are as defined above and m is 0.

The compounds of the formula I according to the invention can be prepared using several methods known per se.

a) In the preparation of compounds of formula I wherein R ¹ and R ² are alkyl or halogen or one of them is hydrogen, R ³ , R ⁴ , R ⁵ , R ⁶ have the same meanings as defined above and R ⁷ is a nitro group, for example a compound of formula II

R ³ R ⁵

O-CH 1 -CH-fCHMCHVNHR ⁶ _(n)

R ⁴ i

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n are as defined above, reacted with 4-nitrophenethyl bromide. This reaction can be carried out with heating and in the absence of a solvent or in various solvents, for example isopropanol, butanol or acetonitrile.

Some of the amino compounds of formula (II) used as starting material are known from the literature (e.g.

BE 626,725; US 3,659,019).

01-1644-00-Ma • 9 • 999

9 9 9

99

9 9

99

9 9 9

Compounds of formula (II) not previously described in the literature can be prepared by known methods. As starting material for the preparation of the novel compounds of the formula II, compounds of the formula V may be used

O-CH 2 CH-CCH 2 CH 3 OH (V) as described in the Examples section.

b) In the preparation of compounds of formula I wherein R ¹ and R ² are alkyl or one of them is hydrogen, R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above and R ⁷ is amino, for example, a compound of formula I in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n are as defined above and R ⁷ is nitro is reduced in a manner known per se. Catalytic hydrogenation or catalytic transfer hydrogenation or another method known in the literature can be used for this reduction.

c) Preparations of compounds of formula I wherein R ¹ and R ² are alkyl or one of them is hydrogen, R ³ , R ⁴ , R ⁵ are as defined above, R ⁶ is alkyl or benzyl, and R ⁷ is alkylsulfonamido, benzamido, alkyl (thio) ureido or aliphatic alkylcarbonylamino (e.g. acetylamino), can be achieved, for example, by reaction of compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is an amino group, with a reagent suitable for

Φ · • Φ • · · ·

01-1644-00-Ma 4

44

44 introduction of a sulfonyl group or with acylating reagents in various solvents.

According to a preferred embodiment of process c) described above, compounds in which R ⁷ is alkylsulfonamido, benzamido or alkylcarbonylamino are reacted with an acid binding reagent (e.g. triethylamine). This reaction is carried out at room temperature or, if necessary, with cooling or heating of the reaction mixture.

According to a further preferred embodiment of process c) described above, the compounds in which R ⁷ is alkyl (thio) ureido are reacted in dioxane in the absence of an acid binding agent at room temperature or with heating.

d) In the preparation of compounds of formula I wherein:

R @ ¹ and R @ ² are alkyl or one of them is hydrogen, R @ ³ , R ^{@ 4} , R @ ⁵ are as defined above, R @ ⁶ is alkyl and R @ ⁷ is alkylamino, e.g. wherein R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, Nam as defined above and ^R7 represents an alkylcarbonylamino group, can be reduced in a known manner.

According to a preferred embodiment of process d), the reaction is carried out using aluminum lithium hydride at the boiling point of tetrahydrofuran.

e) In the preparation of compounds of formula I wherein:

R ¹ and R ² are alkyl, halogen or one of them is hydrogen, R ³ , R ⁴ , R ⁵ are as defined above, R ⁶ is alkyl, hydrogen or benzyl and R ⁷ is methane -1644-00-Ma

0 «* 9 90 9

900 900 · · · 0

0 000 9 9 0 0 9 90 9

0 0 0 0 9 0 000 9 0 0 0 φ * 900 00 0 9000

The sulfonamido group of the formula III is, for example, a compound of the general formula

(III) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , n and m have the previously defined meanings, is reduced in a manner known per se.

According to a preferred embodiment of process e), the reduction is carried out using aluminum lithium hydride in tetrahydrofuran at a temperature corresponding to the boiling point of tetrahydrofuran.

Compounds of formula III used in process e) can be prepared, for example, by reacting amines of formula II with (methanesulfonamido) phenylacetic acid.

According to a preferred embodiment of the above process used to prepare compounds of formula III, the reaction is carried out in N, N-dimethylformamide, in the presence of 4-methylmorpholine, isobutyl chloroformate and triethylamine at -10 ° C and later 0 ° C or tetrahydrofuran in the presence of dicyclohexylcarbodiimide.

f) In the preparation of compounds of formula I wherein R ¹ and R ² are alkyl, halogen or one of them is hydrogen, R ³ , R ⁴ , R ⁵ , R ⁶ have the same meanings as defined above and R ⁷ is a methanesulfonamido group, for example a compound of formula II in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above is reacted with N- [4- (2-bromoethyl)] phenyl] methanesulfonamide.

01-1644-00-Ma • · · 4

4444 4

4 4 4 4 4

4 4 4 4

44

According to a preferred embodiment of process f), the reaction is carried out in the absence of any solvent and with heating.

Salts of the compounds of the formula I according to the invention can be prepared directly in the reaction leading to the preparation of these compounds or, if the compounds of the formula I are isolated in their basic form, the salts can be prepared by dissolving the obtained base in a suitable solvent, e.g. methanol, ethanol, isopropanol, ethyl ether. , ethyl acetate or a mixture thereof, followed by addition to a solution of a suitable acid dissolved in a suitable solvent. The salts can be directly recovered by filtration or optionally precipitation after addition of a suitable solvent, or by total or partial evaporation of the solvent.

It often happens that the salts of the compounds of the formula I according to the invention contain the acid component in a non-stoichiometric ratio and / or crystallize in the form of a hydrate. These crystalline forms are also within the scope of the invention.

The compounds of the formula (I) according to the invention may also optionally contain asymmetric carbon atoms, and these compounds may therefore exist in optically active and racemic modifications. Optically pure compounds can be prepared from optically pure precursors as starting materials or the racemic final product can be resolved. In the latter case, the optical isomers may be isolated by treating the racemic compound, for example in methanol, ethanol, ethyl acetate, acetone, or another solvent, with an optically active acid, for example 0.5 to 2.0 molar amounts of acid (calculated for the compound of formula) I), for example D-tartaric acid, 0,0dibenzoyl-L-tartaric acid, N, N-dimethylnonoamide of 0,0dibenzoyl-D-tartaric acid, L-thiazolidine-4-carboxylic acid

01-1644-00-Ma • ft ftft ftft ftft ·· ftft ftftft ftftftft ftftftft • ftftft ftftftft ftftftft • ftft ftftft · ftftft ftft ftft ftftftftft ftft ftft ftft ftft ftft or other commonly optically active acids, to form a diastereomer salt of one optical isomer in the immediately pure state or optionally after several recrystallizations (depending on the acid used); and the other isomer is obtained by treating the mother liquors in basic form or in the form of their salt (which depends upon the necessity of:

Then, in the case of the isolated salts, the acid addition salts can be obtained by acid.

the amount of acid used), further purified.

of the thus obtained and optically active base by reaction with a therapeutically acceptable

As mentioned above, the compounds of formula I according to the invention exhibit significant antiarrhythmic effects.

In the following, pharmacological results will be discussed which reveal the electrophysiological effects of the compounds of formula I on the heart, which are characteristic of class IB and III compounds, and the absence of negative inotropic effect and induction of arrhythmia, i.e. IB and III are also characteristic. Finally, in vivo, three arrhythmia models will demonstrate the in vivo antiarrhythmic action of compounds of Formula I.

Extracellular electrophysiological measurements

The method used essentially corresponds to that described by Varro et al. [Sheet. Int. Pharmacodyn. Ther. 292,

157-165 (1988)].

01-1644-00-Ma • 3 ···

4 4 44

. 9 4 9 4 9 4

9444 44 4 9949

44 44 44 44

Right ventricular trabeculae were dissected from the hearts of mixed race dogs (each weighing 5-10 kg). Surviving heart pieces were placed in an organ bath (37 ° C) containing modified Tyrode nutrient medium and excited by spot stimulation at a basal frequency of 1 Hz. Extra-cellular bipolar platinum electrodes were placed on the surface of the specimen, which recorded propagation of surface potentials and thus determined the time of impulse transmission, respectively. pulse transfer rate, and allow an effective refractive period (ERP). During the experiment, the pacing rate temporarily changed from 0.5 Hz to 3 Hz. After dilution of the stock solution to the desired final concentration, test compounds were added directly to the organ bath. The effects of the compounds were observed after a 30-40 minute incubation period.

The results of extracellular in vitro electrophysiological measurements of the heart are shown in Table 1.

Table 1

Observed effects of compounds on impulse transmission and effective refractive period (ERP) on isolated right ventricular trabeculae of dog heart

Example Extension (%) of the pulse transfer time ERP extension (%) (10 μΜ) Ν 1 Hz 3 Hz 1 Hz 3 Hz 9 (2 μΜ) 12 +38,013,5 +51,314,9 131.812.5 + 39.4 + 5.0 15 Dec 16 142.0 + 7.5 + 73.8 + 8.3 122,811,3 + 31.3 + 1.6 15 (2 μΜ) 8 + 11.1 + 2.2 +13,412,8 111.611.2 + 13.6 + 2.9 16 12 + 26.9 + 3.1 +39,713,1 +10,710,7 + 14.3 + 1.7 17 12 + 32.5 ± 6.0 +35,115,9 112.1 + 0.9 + 17.1 + 2.1

01-1644-00-Ma • Φ φ φ φ φ φ φ »φ • φ • • • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Example Extension (%) of the pulse transfer time ERP extension (%) (10 μΜ) N 1 Hz 3 Hz 1 Hz 3 Hz 18 12 + 18.5 + 2.4 + 21.7 + 4.0 + 9.9 + 0.8 + 14.0 + 1.3 20 May 12 + 20.3 + 2.7 + 24.5 + 3.5 + 8.4 + 0.3 + 12.6 + 0.6 22nd 12 + 22.6 + 4.1 + 28.3 + 5.3 + 12.3 + 1.3 + 18.1 + 1.8 23 12 + 25.0 + 3.9 + 25.0 + 4.2 + 10.8 + 1.1 + 14.9 + 1.4 24 12 + 69.0 + 11.9 + 82.9 + 11.0 + 13.8 + 1.7 + 18.4 + 1.2 25 12 + 18.8 + 2.0 + 18.8 + 3.1 + 11.7 + 1.2 + 17.0 + 1.3 Mexiletine (10 μΜ) 6 + 3.9 + 1.8 + 18.8 + 2.5 -1.9 + 1.7 + 8.9 + 5.4 d-Sotalol (30 μΜ) 8 -4.5 + 5.1 -3.7 + 4.7 + 12.4 + 2.3 + 7.1 + 2.7

Ν: Total number of animals per group.

Among the test compounds, the compounds of Examples 9, 15, 16, 17 and 24, which substantially prolonged the pulse transmission time in a frequency dependent manner, i.e., slowed the pulse transmission while prolonging the effective refractive period (ERP). Mexiletine (chemical designation 2 (2,6-dimethylphenoxy) -1-methylethylamine hydrochloride), used as a reference substance, showed an effect mainly on impulse transmission, whereas d-sotalol had a great effect only on ERP.

Intracellular electrode techniques

The method used is essentially the same as that described by Papp et al. [J. Cardiovascular Pharmacol. Ther. 1,

287-296 (1996)].

01-1644-00-Ma

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I 9 999

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9

9

Right ventricular papillary muscle and Purkinje fiber were dissected from the hearts of mixed race dogs (each weighing 5-10 kg). Surviving heart pieces were placed in an organ bath (37 ° C) containing modified Tyrode nutrient medium and excited by spot stimulation at a basal frequency of 1 Hz. During the experiment, the pacing rate varied over a wide range, using a computer-controlled stimulator. Intracellular action potentials were recorded using glass capillary microelectrodes filled with 3N potassium chloride solution (standard intracellular microelectrode techniques). Remaining Potential (RP), Action Potential Amplitude (APA) as well as Action Potential Duration (APD) were measured using a compatible IBM 386 computer and self-developed software. After dilution of the stock solutions to the desired final concentrations, test compounds were added directly to the organ bath. The effects of the compounds were observed after a 30-40 minute incubation period.

The results of intracellular electrophysiological measurements performed on cardiac papillary muscle are summarized in Table 2. Of the test compounds, the compounds of Examples 9, 14, 15, 16, 17, 22, 26 and 27 showed a V _max- like mexiletine inhibition which can be characterized by relatively high degrees of rapid regeneration kinetics, while increasing the duration of action potential (APD) (an effect similar to that of dofetilide, whose chemical name is N- [4- [2- [N-methyl-N- [2- (4-methanesulfonamidophenoxy) ethyl]] amino] ethyl] phenyl] methanesulfonamide). No significant differences were observed between the effects of the compound of Example 15 and its enantiomers (Examples 16 and 17) in this experiment.

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depolarization rate; T _re g _en eratio ns: regeneration time constant, V _max; Gy: fast kinetics

01-1644-00-Ma •

The effects of the test compounds of the invention on the action potential of Purkinje fibers isolated from the dog's heart are summarized in Tables 3 and 4 for the compound of Example 15.

The compound of Example 15 (5 μΜ) prolonged the APD in the dog's ventricular muscle and concomitantly shortened the APD on the Purkinje fibers of the dog at concentrations of 2 μΜ and 5 μΜ. This result is very important because it can be expected that the compound will not increase but rather reduce the inhomogeneity of ventricular repolarization (which is an important proarrhythmic factor).

Table 3

Effect of the compound of Example 15 on the action potential of Purkinje fibers isolated from the dog's heart

Parameter N Checklist Example 15 2 μΜ MDP (mV) 3 -82.0 + 2.1 -81.7 + 2.4 APA (mV) 3 11.3 + 3.8 112.7 + 3.9 APD ₅₀ (ms) 3 261.7 + 36.2 180.7 + 14.8 APDgo (ms) 3 468.0 + 81.1 400.0 + 47.4 V _max (V / sec) 3 397.3 + 25.4 392.3 + 23.7

MDD: maximum diastolic potential;

APA: action potential amplitude;

N:

APD ₅₀ : 50% repolarization time;

APDgo: 90% repolarization time;

V _max : maximum depolarization rate;

total number of animals per group.

• ·

01-1644-00-Ma •

Table 4

Effect of Example 15 (5 μΜ) on Action Potential on Ventricular Muscle and Purkinje Fibers of Dog Heart at 1 Hz Pacing Rate

Parameter Ventricular muscle Purkyně's thread Checklist Example 15 Checklist Example 15 N = 6 N = 6 RP (mV) -84.3 + 1.4 -84.5 + 1.3 -87.7 + 1.3 -86.0 + 2.0 APA (mV) 106.8 + 2.2 106.3 + 2.0 118.7 + 0.9 11.0 + 2.4 * APD ₅₀ (ms) 195.0 + 6.7 209.5 + 7.1 * 313.5 + 26.0 121.3 + 13.8 * APDgo (ms) 234.2 + 9.4 260.5 + 6.5 * 461.5 + 26.5 279.0 + 11.2 * Vnax (V / sec) 203.0 + 3.5 203.0 + 11.4 575.5 + 35.9 439.3 + 34.4 * Vmax Regeneration time T (ms) <30 ms 270.1 + 14.4 Vitax Recovery time amplitude (V / s) - 83.6 + 13.5 35 + 5% - - Vmax Plato · regeneration phase (V / s) - 245.5 + 28.0 - -

* p <0.05 N: Total number of animals per group.

Determination of the effect immediately after depolarization (Fig. 1) in the early period after depolarization

Early post-depolarization (EAD) was induced on Purkinje fibers by concomitant use of 1 μΜ dofetilide and 20 μΜ barium chloride. This EAD was abolished by adding the compound (2 μΜ) of Example 15. The result of these experiments suggests that unlike d-sotalol, the compound of Example 15 could not be expected to induce

01-1644-00-Ma torsade de pointes, ie proarrhythmic complications associated with prolonged repolarization.

In vitro contractile force measurement

The method used was essentially the same as that described by Virág et al. [Gene. Pharmac., 27, pp. 551-556 (1996)].

A ventricular papillary muscle was dissected from the hearts of rabbits (2 to 3 kg each) and placed in an organ bath (37 ° C) containing modified Tyrode's nutrient medium and excited by point stimulation at a basal frequency of 1 Hz. measured using an auxotonic method. After dilution of the stock solution according to the desired final concentration, test compounds were directly added to the organ bath. The effects of the compounds were observed after a 30 min to 45 min incubation period.

This method provides information on the direct effect of the test compounds on the heart. The effect of the compound of Example 15 on contractile force is illustrated in the right ventricular papillary muscle at 1 Hz in Fig. 2. The results show that the expected therapeutic concentration of the compound of Example 15 does not induce any negative inotropic effect since the contractile force of the papillary muscle when using a concentration lower than 30 μΜ did not decrease.

01-1644-00-Ma 4 4 *

4 4 · · · · · ·

Acute toxicity

Determination of LD ₅₀ value in mice

Animal: male (fasted) CDI mice weighing 20-22 g at the time of treatment.

Observation period: 2 weeks.

Vehicle: 1% to 2% Tween 80 solution in distilled water, respectively. physiological saline solution.

Treatment dose: 0.1 ml / 10 g body weight.

The results are summarized in Table 5.

Table 5

Acute toxicity of the test compound of Example 15 and mexiletine used as reference

Compound Way filed Concentration (mg / kg) Mortality LD50 (mg / kg) (cause of death) Example 15 i.p. 150 175 200 1/10 7/10 9/10 170.4 (154.3-188.2) (respiratory paralysis) after. 500 600 700 0/5 2/5 5/5 550-650 (respiratory paralysis) Mexiletine i.p. 130 (respiratory paralysis) after. 300 (respiratory paralysis)

01-1644-00-Ma •

Evaluation of occlusion and reperfusion-induced arrhythmia following acute coronary arterial ligation in anesthetized rabbits

The method used is essentially the same as that described by Thiemermann et al. [Br. J. Pharmacol. 97, p. 401408 (1989)].

After thoracotomy in male rabbits (2 kg to 3 kg) anesthetized with pentobarbital (30 mg / kg i.v.), a loose loop of surgical thread was wrapped around the curved left heart artery, with both ends of the loop extending from the chest through an elastic tube. A standard electrocardiogram was recorded using needle electrodes inserted under the skin. Animal blood pressure was continuously measured using a catheter placed in the cervical artery. After the blood pressure and heart rate had stabilized, the loose loop tightened, causing local ischemia of the heart muscle. After 10 minutes of ischemia, the ligation relaxed and reperfusion occurred within 10 minutes. Survival, incidence of arrhythmias, time of onset and duration of arrhythmia were noted. The animals received intravenous saline (control) (2 ml / kg) or 0.03 mg / kg of the compound of Example 15 or 3 mg / kg d-sotalol intravenously 5 minutes before the occlusion.

Using this method, it can be determined whether the test compound will provide effective protection against arrhythmias following coronary arterial ligation. Experiments performed (see Tables 6 and 7) indicated that the compound of Example 15, administered at a dose of 0.03 mg / kg, showed a potent antiarrhythmic effect in rabbits that counteract ligation-induced reperfusion arrhythmias.

01-1644-00-Ma

Table

01-1644-00-Ma • 9b

* 9 • 9

Evaluation of occlusion and reperfusion arrhythmia following acute coronary ligation in anesthetized dogs

The method used is essentially the same as that described by Végh et al. [Basic Res. Cardiol. 82, 159-171 (1987)].

Mixed race dogs of both sexes weighing 10-20 kg were anesthetized with a mixture of chloralose (60 mg / kg) and urethane (200 mg / kg) and maintained on artificial respiration. When the chest was opened, the left coronary artery anterior branch (LAD) was dissected from the first major collateral branch and a loose loop of surgical thread wrapped around it. During the experiments, animal blood pressure was measured using a cannula inserted into the left femoral artery, and standard ECG parameters were even continuously recorded using needle electrodes. Arrhythmias were induced by a 25-minute occlusion caused by tightening the loop wrapped around the LAD. Survival after deadly arrhythmias and frequency of arrhythmias were recorded. The 28 dogs used in the experiments were divided into three groups: Eight animals were dosed with 1 mg / kg of the compound of Example 15; Ten animals received 3 mg / kg d-sotalol as a single intravenous injection ten minutes prior to coronary artery compression. Ten control animals received 5 ml of physiological saline in the same manner as the treated animals.

Using this method, it was possible to determine whether the test substance would be effective in protecting against arrhythmias following ligation of the coronary artery. Experiments carried out indicated (Table 8) that the protection afforded by the 1 mg / kg dose of Example 15 from the arrhythmic effects of coronary artery ligation and reperfusion is higher than the protection afforded by the 3 mg / kg dose

01-1644-00-Ma d-sotalol, indicating that this compound has high antiarrhythmic activity.

Table 8

Evaluation of occlusion and reperfusion arrhythmia following acute compression in anesthetized dogs

Compound N Occlusion Reperfusion VF Overall survival EC VT VF Checklist 10 327122 10/10 100% 6/10 60% 4/4 100% 0/7 0% d-Sotalol (3mg / kg) 10 128114 5/10 50% 3/10 30% 2/7 29% 5/10 50% Example 15 (1 mg / kg) 8 36.6184.1 1/8 12.5% 1/8 12.5% 0/7 0% 7/8 87.5% ES: extrasysto ( .and; VT: ventilator ( .arry tachycardia; VF: out-

tricular fibrillation; N: total number of animals per group.

Occlusion arrhythmia following acute ligation of coronary artery in conscious rats

The method used is essentially the same as that described by Lepran et al. [J. Pharmacol. Methods 9, pp. 219-230 (1983)].

During the operation prior to testing, male rats weighing 340-360 g wrapped a loose loop of surgical thread around the left descending coronary vessel, at a location approximately 2 mm from its start. The ends of the loop that came out of the chest under the skin were then covered with a surgical bandage. After complete recovery from this operation (7 to 8 days) in conscious animals

01-1644-00-Ma fc · ·· • 9 9 • fcfcfcfc · ·· ·· · fc

Fcfc fc fc fcfc fcfc fcfc induced acute cardiac muscle ischemia by tightening free ligature. ECG was continuously recorded with bipolar thoracic electrodes both before coronary artery ligation and during the first 15 minutes of ischemia. Survival rates were determined and the arrhythmias developed were evaluated according to the Lambeth convention [Walker et al .: Cardiovasc. Res. 22, pp. 447-455 (1988)]. A rating system was also used to evaluate arrhythmic episodes, where individual episodes were evaluated for severity from 0 to 6. Both d-sotalol and the compound of Example 15 were suspended in a 1% methylcellulose solution and were administered orally by gavage one hour before coronary artery compression. Control animals were treated with an equal volume, i.e. 5 ml / kg of vehicle.

In conscious rats representing a model of arrhythmia following acute coronary artery occlusion, the compound showed a mechanism of action) administration, whereas the combined after oral prolongation of Example 15 (having antiarrhythmic effect also d-sotalol, which only repolarization, appeared to be Another advantage of using the compound of Example 15 is that at 25 mg / kg, the heart rate did not change statistically during the first 15 minutes of myocardial infarction, whereas it slowed by approximately 15% in the untreated control group.

• · ftft

01-1644-00-Ma ft ft

· Ft · ft · ft · ft · ft · ft 999 · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft · ft

Effects on Survival and Incidence of Azytia in Scientific Rat Models Pre-Treated with d-sotalol or Example 15 Run the First 15 Minutes of Ischemia Following Coronary Artery Occlusion

Φ • H £ Evaluation 1 Γ CM O +1 in * IN) TO. O +1 Oů TO. what OO rH with. O +1 rH r- TO LO O O +1 O Brady 3/19 2/12 2/29 1/10 n /% Other 8/50 9/56 3/43 ^! 4/40 Ή • H & d VT 15/94 12/75 7/100 10/100 • P & (0 £ E 15/94 10/63 * 7/100 1/100 Negative 0/0 3/19 0/0 0/0 Survival 16 hrs n /% 3/19 2/29 ' 0/0 fi <ΙΟ ^β rH 4/25 8/50 2/29 1/10 % 16 16 r ~ O rH Group Checklist Example 15 compound after. 25 mg / kg d-Sotalol after. 25 mg / kg d-Sotalol · after. 50 mg / kg

N: total number of animals per group; n: number of animals providing adequate response; Negative: no arrhythmia observed; VF: ventricular fibrillation; VT: ventricular tachycardia; Other: ventricular extrasystola, bigemins, salvo; Brady: bradycardia. The asterisk indicates a statistically significant deviation: P <0.05.

01-1644-00-Ma

Φ Φ φ · • φ φ φ φ φ φ φ φ • • • φ φ φ φ

ΦΦΦΦΦ φφ φ φ φφφφ φφ φφ φφ

The compounds of the invention can be used to eliminate cardiac arrhythmias in humans.

used in mammals including

For therapeutic purposes, the compounds of the invention and their therapeutically acceptable salts can be used alone or in the form of pharmaceutical compositions. The invention also relates to such compositions.

These pharmaceutical compositions contain an effective amount of a compound of Formula I or a therapeutically acceptable salt thereof as an active ingredient in admixture with excipients, fillers, diluents and / or other pharmaceutical excipients commonly used in the manufacture of medicaments.

Suitable carriers, diluents or fillers may be water, alcohols, gelatin, lactose, sucrose, starch, pectin, magnesium stearate, stearic acid, talc, various oils of vegetable or animal origin, as well as glycols such as propylene glycol or polyethylene glycol. Auxiliary pharmaceutical additives are, for example, stabilizers, antioxidants, various natural or synthetic emulsifying, dispersing or wetting agents, coloring agents, flavoring agents, buffers, disintegrating agents and other substances promoting the bioavailability of the active ingredients.

The pharmaceutical compositions of the invention may be used in conventional pharmaceutical dosage forms. Such suitable dosage forms are, for example, oral compositions (administered by the oral route), prepared using pharmaceutical excipients. These compositions are either in solid form, for example tablets, capsules, powders, pills, dragees, or granules; or a liquid form such as syrups, emulsions or suspensions. Another form of compositions is rectal

01-1644-00-Ma ·· · Φ · Φ · · 4 · 9 4 9 • Φ · · · · · · · · · · · · · · · · · · · · · · · · * Compositions such as suppositories (which can be administered by the rectal route); and parenteral compositions (administered bypassing the gastrointestinal system), such as by injection or infusion.

Although the doses of the compounds of the invention required to achieve a therapeutic effect depend on the individual condition and age of the patient and are ultimately determined by the physician, the daily dose of the compound required for the treatment of arrhythmia-associated diseases is administered orally or parenterally, e.g. , from about 0.1 mg to 5.0 mg, preferably from about 0.1 mg to 2.0 mg, calculated for 1 kg body weight.

The compounds of the invention and methods for their preparation will be illustrated in the following examples. It is to be understood that these examples are illustrative only and are not to be construed as limiting the scope of the invention as set forth in the appended claims.

Examples of embodiments of the invention

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-methylethylamine (BE 626,725) in 40 ml of isopropanol is added 7.13 g (31 mmol) of 4-nitrophenethyl bromide and the reaction the mixture was refluxed for 5 hours. After evaporation of the solvent, the residue was triturated with 20 ml of ethyl acetate. The precipitated amine hydrobromide is filtered off and rinsed with ethyl acetate. After evaporation

01-1644-00-Ma

949

9

9 4 9

944-9 of the solvent gave the crude product (base) which was purified by column chromatography (eluent: dichloromethane and methanol = 9: 0.1). A total of (hydrochloride salt) 0.88 g (7.5%) of white crystalline product was obtained, m.p .: 135-138 ° C.

^X HMR (CDCl3, very dilute solution): 1.15 (m, 3H, _C-CH3); 2.25 (s, 6H, Ar-o-CH3); 2, 90-4,20 (m, 10H, _0-CH2-CH-U, NCH _3, NCH ₂ CH ₂ -Ar); 6.85-7.10 (m, 3H, Ar); 7.48 (d, 2H) and 8.20 (d, 2H) (Ar); 13.0 (br. 1H, NH &lt; ⁺ & gt ^; ).

Example 2

N- [2- (2,6-Dimethylphenoxy) ethyl] -N-methyl-2- (4-nitrophenyl) ethylamine hydrochloride

The title compound was prepared as described in Example 1 except that N-methyl-2- (2,6-dimethylphenoxy) ethylamine (BE 626.725) was used as the starting material. There was thus obtained the title compound (HCl salt) as a white crystalline product in 30% yield, mp: 147-149 ° C.

¹ H NMR (DMSO-d 6): 2.22 (s, 6H, Ar-CH ₃ ); 2.96 (d, 3H, NCH _3); 3.20-3.80 (m, 6H, CH ₂ -CF ₂ -N-CH ₂ -CH ₂ -kr); 4.05-4.25 (m, 2H, O-CH2-CH2); 6.70-7.00 (m, 3H, Ar); 7.55 (d, 2H) and 8.15 (d, 2H) (p-nitrophenyl); 11.54 (br. 1H, NH &lt; ⁺ & gt ^; ).

01-1644-00-Ma

99 99 99

9 9 9

9 9 9 9 9 9

9 9 99 99 99 9

9 9 9 9 9

99 99 99

mp .:

CH ₃ );

· · ♦ ♦ ♦ · · «« ·

99

Example 3

N-Methyl-N- [2- (2,6-methylphenoxy) ethyl] -2- (4-nitrophenyl) ethylamine hydrochloride

The title compound was prepared as described in Example 1 except that N-methyl-2- (2-methylphenoxy) ethylamine was used as the starting material (Example 43). There was thus obtained the title compound (hydrochloride as a white crystalline product in 28% yield).

137-138 ° C.

1 H NMR (DMSO-d ₆ ): 2.12 (s, 6H, Ar-CH ₃ ); 2.95 (d, 3H, N 3.28 (t, 2H, CH ₂ -Ctf ₂ -Ar); 3.35-3.80 (m, 4H, Ct F ₂ -N.4.42 (t, 2H, O-) CH ₂ -CH ₂ ), 6.80-7.20 (m, 4H, Ar); 7.60 (d, 2H) and 8.22 (d, 2H) (p-nitrophenyl); 11.25 (br (1H, NH &lt; ⁺ & gt ^; ).

Example 4 (S) -N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine

The title compound was prepared as described in Example 1, except that (S) -N-methyl-2- (2,6-dimethyl-phenoxy) -1-methylethylamine was used as the starting material (Example 47). An oily substance was prepared in 17% yield (base) containing 1% R-enantiomer as determined by chiral HPLC analysis (Chiralcel OJ column), Rf = 0.7 (ethyl acetate / methanol = 9: 1).

01-1644-00-Ma • 4

4 «44

4 4 4

4 4 4

4 4 • 4

4 4

4

4

4

4 4

4 ·

44

Example 5 (R) -N- [2- (2,6-Dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine

The title compound was prepared as described in Example 1, except that (R) -N-methyl-2- (2, β-dimethylphenoxy) -1-methylethylamine was used as the starting material (Example 46). In this way, an oil was prepared in 17% yield (base) containing no S-enantiomer as determined by chiral HPLC analysis (Chiralcel OJ column), Rf-0.7 (ethyl acetate / methanol = 9: 1).

Example 6

N-Methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-nitrophenyl) ethylamine hydrochloride

The title compound was prepared as described in Example 1 except that N-methyl-2- (2-methylphenoxy) -1-methylethylamine was used as the starting material (Example 48). There was thus obtained the title compound (HCl salt) as white crystals in 14% yield, mp: 140-142 ° C.

1 H NMR (DMSO-d ₆ ): 1.45 (m, 3H, C-CH ₃ ); 2.10 (s) and 2.20 (s) (total 3H, _Ar-CH3); 2.88 (m, 3H, N-CH _3); 3.20-3.60 (m,

4H, _{N-CH2 -CH2} -Ar); 3.92 (m, 1H, CH ₂ -CH-N); 4.35 (m, 2H, -CH ₂ 0CH); 6.80-7.20 (m, 4H, Ar); 7.60 (m, 2H) and 8.22 (d,

2H) (Ar); 11.20 (br. S, 1H, NH &lt; ⁺ & gt ^; ).

01-1644-00-Ma ··

0 0

0 * 00 0 0

0 0 0

00

00 0 0 0 ·

0 0 *

0 »00

0 *

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0 0 0

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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 suspension 0. 1 g of 10% palladium on carbon catalyst in 7 ml of isopropanol. The suspension is hydrogenated at atmospheric pressure. After completion of the reaction, the catalyst is filtered off and rinsed with isopropanol. The filtrate was evaporated under reduced pressure to constant weight to give 0.37 g of an oil base (76% yield), Rf = 0.35 (ethyl acetate / methanol = 9: 1).

Example 8

N-Methyl-N- [2- (2-methylphenoxy) ethyl] -2- (4-aminophenyl) ethylamine

The title compound was prepared according to the procedure in Example 7, except that N- [2- (2-methyl-phenoxy) -ethyl] -N-methyl-2- (4-nitrophenyl) -ethylamine was used as the starting material (Example 3). This gave the base (oil) in 82% yield, Rf = 0.35 (ethyl acetate / methanol = 9.1).

01-1644-00-Ma · ř 99 • • • • • • • 99 99 99 99

99 ♦ · ··· · · ·

9 ·· 999 ·

9,999 9,999 9

9 9 9 9 9

99 99 99

Example 9

N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine

The title compound was prepared as described in Example 7, except that N- [2- (2, β-dimethylphenoxy) 1-methylethyl] -N-methyl-2- (4-nitrophenyl) ethylamine was used as the starting material (Example 1). The oil base was obtained in 90% yield.

1 H NMR (CDCl ₃ ): 1.25 (d, 3H, C-CH ₃ ); 22.32 (s, 6H, ARCH ₃ ); 2.48 (s, 3H, N-CH _3); 2, 65-2,85 (m, 4H, _{N-CH2 -CH2} -Ar);

3.28 (m, 1H, CH ₂ N -Ctf); 3.2-3.8 (br. S, 2H, NH _2); 3.65 (dd, J = 9.2 and 6.7 Hz, 1H) and 3.92 (dd, J = 9.2 and 5.7 Hz, 1H) (O-CH2-CH); 6.66 (d, 2H, Ar); 6.9-7.10 (m, 5H, Ar).

Example 10 (S) -N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) -ethylamine

The title compound was prepared according to the procedure in Example 7, except that (S) -N- [2- (2,6-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) was used as the starting material. ethylamine (Example 4). By this method a white oil is prepared in 93% yield (base) containing 1% to 2% of the R-enantiomer as determined by chiral HPLC analysis (Chiralcel OJ column), Rf = 0.35 (ethyl acetate / methanol = 9: 1) .

·· • · ·

9 9

9 9

9 9

01-1645-00-Ma · «•

999 9 O 99 O O O O O O O 99 O 99

99

Example 11 (R) -N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine

The title compound was prepared according to the procedure in Example 7, except that (R) -N- [2- (2,6-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-nitrophenyl) was used as the starting material. ethylamine (Example 5). In this way, a white oil base was obtained in 89% yield containing 1% of the S-enantiomer as determined by chiral HPLC analysis (Chiralcel OJ column), Rf = 0.35 (ethyl acetate / methanol = 9: 1).

Example 12

N-Methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-aminophenyl) ethylamine

The title compound was prepared as described in Example 7, except that N-methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-nitrophenyl) ethylamine was used as the starting material (Example 6). An oil base is obtained in 89% yield.

¹ H NMR (CDCl 3): 1.16 (d, 3H, C-CH ₃ ); 2.20 (s, 3H, ArCH _3); 2.40 (s, 3H, N-CH _3); 2.60-2.80 (m, 4H, _N-CH2 -Ar -C7í _2);

3, 30-3,70 (br. S, 2H, NH _2); 3.70 (m, 1H, CH ₂ -CH ₂ -N); 3.82 (dd, 1H) and 4.02 (dd, 1H) (O-CH ₂ -CH); 6.60 (d, 2H) and 7.00 (d,

2H) (p-aminophenyl); 6.72-6, 90 (m, 2H) and 7.08-7.20 (m,

2H) (Ar).

01-1644-00-Ma

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 is added 0, 50 g (4.95 mmol) of triethylamine are added dropwise to this solution, cooled to 0 ° C at the same temperature.

0.63 g (5.5 mmol) of methanesulfonyl chloride. After stirring the reaction mixture at 0 ° C for 1 hour and rinsing with 30 ml of saturated sodium bicarbonate solution, the aqueous phase is extracted twice with 20 ml of dichloromethane. The combined organic phase was washed twice with 30 ml of water, dried and evaporated to give 0.44 g (94% yield) of an oil base. The yield of the hydrochloride salt was 0.244 g (47% yield) of white crystals, m.p. Mp 168-169 ° C.

¹ H NMR (DMSO-c / g): 2.25 (s, 6H, Ar-CH ₃ ); 2.95 (s, 6H, NCH ₃ and S-CH ₃ overlap); 3.10 (t, 2H, CH ₂ -CH ₂ -Ar); 3.25-3.75 (m, 4H, CH2-N-CH2} 4.15 (t, 2H, _O-2 CIR -CH _2), 6, 85-7,05 (m, 3H, Ar) 7.14 (d, 2H) and 7.24 (d, 2H) (4-methanesulfonamidophenyl); 9.75 (s, 1H, Ar-NH-S); 11.20 (br. 1H, NH ⁺ ) .

Example 14

N- [4- [2- [N-Methyl-N- [2- (2-methylphenoxy) ethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared as described in Example 13 except that N-methyl-N- [2- (2-methyl-phenoxy) -ethyl] -2- (4-amino-01-1644-00-Ma) was used as the starting material. · ··· ···· · · · ·

.......... · ·! j:

Phenyl) ethylamine (Example 8). There was thus obtained the hydrochloride salt as white crystals in 71% yield, m.p. Mp 180-181 ° C.

^X HMR (DMSO-d₆): 2.15 (s, 3H, _Ar-CH3); 2.90 (d, 3H, NCH _3); 2.95 (s, 3H, _S-CH3); 3.10 (t, 2H, CH ₂ -CH ₂ -Ar); 3253.80 (m, 4H, _{CH2 -N-CH2);} 4.44 (t, 2H, 0-CH ₂ -CH _2); 6.80-7.00 (m, 2H, Ar) and 7.15-7.30 (m, 6H) (Ar); 9.75 (s, 1H, Ar - NH - S); 11.20 (br. 1H, NH &lt; ⁺ & gt ^; ).

Example 15

N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared as described in Example 13, except that N- [2- (2,6-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) -ethylamine was used as the starting material (Example 9). ). There was thus obtained the hydrochloride salt as white crystals in 56% yield, m.p. Mp 224-227 ° C.

¹ H NMR (DMSO-d 6, at room temperature): 1.45 (m, 3H, CCH ₃ ); 2.28 (s, 6H, _Ar-o-CH3); 2.90 (m, 3H, N-CH _3); 2.96 (s, 3H, _S-CH3); 3.00-3.50 (m, 4H, _{N-CH2 -CH2} -Ar); 3.90 (m, IH,

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); 9.75 (s, 1H, Ar - NH - S); 10.90 (br. S, 1H, NH &lt; ⁺ & gt ^; ).

01-1644-00-Ma

Example 16 (S) -N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared according to the procedure in Example 13, except that (S) -N- [2- (2,6-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) was used as the starting material. ethylamine (Example 10). There was thus obtained the hydrochloride salt as white crystals in 63% yield, m.p. Mp 192-193 ° C.

Chiral HPLC analysis (Chiralcel OJ column) showed that this product contained no R-enantiomer.

¹ H NMR (DMSO-d 6, at room temperature): 1.45 (m, 3H, CCH ₃ ); 2.28 (s, 6H, _Ar-o-CH3); 2.90 (m, 3H, N-CH _3); 2.96 (s, 3H, _S-CH3); 3.00-3.50 (m, 4H, _{N-CH2 -CH2} -Ar); 3.90 (m, IH,

CH ₂ -CH-N); 3.98-4.16 (m, 2H, O-Cl ₂ -CH); 6.90-7.10 (m, 3H,

Ar); 7.14-7.32 (m, 4H, Ar); 9.70 (s, 1H, 1H-NH-S); 10.75 (br. S, 1H, NH &lt; ⁺ & gt ^; ).

¹ H NMR (DMSO-d 6, 100 ° C): 1.45 (m, 3H, C-CH ₃ ); 2.28 (s,

6H, _Ar-o-CH3); 2.88 (s, 3H, N-CH _3); 2.96 (s, 3H, _S-CH3);

3.00-3.50 (m, 4H, N-Cef ₂ -C% -Ar); 3.85 (m, 1H, CH ₂ -CH-N); 4.04 (dd, J = 10.6 and 5.1 Hz, 1H) and 4.14 (dd, J = 10.6 and 5.6 Hz, 1H) (O-Cl-CH); 6.90-7.06 (m, 3H, Ar); 7.16-7.30 (m, 4H, Ar); 9.35 (s, 1H, 1H-NH-S); 11.00 (br. S, 1H, NH &lt; ⁺ & gt ^; ).

01-1644-00-Ma

Example 17 (R) -N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared according to the procedure in Example 13, except that (R) -N- [2- (2,6-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) was used as the starting material. ethylamine (Example 11). The hydrochloride salt is thus obtained in the form of white crystals in 55% yield, m.p. 190-191 ° C.

Chiral HPLC analysis (Chiralcel OJ column) showed that this product contained no S-enantiomer.

¹ H NMR (DMSO-c / g, at room temperature): 1.45 (m, 3H, CCH ₃ ) and 2.28 (s, 6H, Ar-o-CH ₃ ); 2.90 (m, 3H, N-CH _3); 2.96 (s, 3H, _S-CH3); 3.00-3.50 (m, 4H, _{N-CH2 -CH2} -Ar); 3.90 (m, IH,

CH ₂ -CH-N); 3.98-4.16 (m, 2H, O-CH ₂ -CH); 6.90-7.10 (m, 3H,

Ar); 7.14-7.32 (m, 4H, Ar); 9.70 (s, 1H, Ar - NH - S); 10.75 (br. S, 1H, NH &lt; ⁺ & gt ^; ).

Example 18

N- [4- [2- [N-Methyl-N- [2- (2-methylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared as described in Example 13, except that N-methyl-N- [2- (2-methylphenoxy) -1-methylethyl] -2- (4-aminophenyl) ethylamine was used as the starting material (Example 12). There was thus obtained the hydrochloride salt as white crystals in 60% yield, m.p. Mp 165-167 ° C.

01-1644-00-Ma • ··· «· · · · ·

........:!

¹ H NMR (DMSO-d 6): 1.38-1.52 (m, 3H, C-CH ₃₎ ); 2.10 (s) a

2.20 (s) (total 3H, _Ar-CH3); 2.85 (m, 3H, N-CH _3); 2.96 (s, 3H, _S-CH3); 3, 05-3,50 (m, 4H, CH-R ₂ -CH ₂ -] \ r); 3.94 (m, 1 H,

CH ₂ -OT-N); 4.20-4.40 (m, 2H, O-CH ₂ -CR); 6.70-7.00 (m, 2H) and 7.10-7.35 (m, 6H) (Ar); 7.92 (s, 1H, Ar-N 1 -S); 10.70-11.00 (br. 1H, NH ⁺ ).

Example 19

N- [4- [2- [N-Methyl-N- [2- (2,3-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

To a solution containing 0.82 g (2 mmol) of N- [2- (2,3-dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) acetamide (Example 50) in 20 mL of anhydrous tetrahydrofuran was added 0.10 g of lithium aluminum hydride (LAH) and the mixture was boiled for approximately 1 hour to complete the reaction. Progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, excess reagent was quenched by addition of ethyl acetate, 10% sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The combined organic phase is washed with water and then extracted with 2N aqueous hydrochloric acid. The acidic phase is basified to pH 9 by addition of 10% sodium hydroxide solution and then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried, and the solvent was evaporated under reduced pressure to give 0.56 g of a thick oil as a residue. This crude product is purified, if necessary, by column chromatography eluting with 2: 1 or 1: 1 hexane: ethyl acetate. 0.38 g Hydrochloride

44

4 4

4 4 44

4 4 4

44 • 4

01-1644-00-Ma salt was obtained as amorphous white flakes (45% yield).

^X HMR (DMSO-c / GJ: 1.40-1.50 (m, 3H, _C-CH3); 2.00 (s), and

2.08 (s) and 2.22 (s) (total N-CH ₃ ); 2.95 (s, 3H, _S-CH3);

Ar); 3.92 (m, 1H, CH ₂ -CH-N);

6.75 to 7.30 (m, 2H, _0-CH2-CN);

(s, 1H, Ar-WH-S); 10.8 to 11.1 _(Ar-CH3); 2.80-2.90 (m, 3H,

3,00-3,50 (m, 4H, n-ch ₂ -ch ₂ - 4,25-4,35 (m, 2H, O-C 7 H 2 -CH); 6.75-7.30 (m, 7H, Ar); 7.95

(1H, NH &lt; ⁺ & gt ^; ).

Example 20

N- [4- [2- [N-Methyl-N- [2- (2,5-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared according to the procedure in Example 19, except that N- [2- (2,5-dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) -acetamide was used as the starting material (Example 51). ). The hydrochloride salt was obtained as an amorphous white precipitate in 40% yield.

^X HMR (DMSO- d): 1, 40-1,50 (m, 3H, _C-CH3); 2.00 (s), 2.10 (s), 2.25 (s) and 2.26 (s) (total 6H, Ar-CH ₃ ); 2802.90 (m, 3H, N-CH _3); 2.95 (s, 3H, _S-CH3); 3.00-3.50 (m, 4H, N-Cl-CH2-Ar); 3.92 (m, 1H, CH ₂ -CH-N); 4.20-4.35 (m, 2H, OCl2-CH); 6.60-7.30 (m, 7H, Ar); 7.95 (s, 1H, Ar - NH - S);

10.65-11.00 (m, 1H, NH &lt; ⁺ & gt ^; ).

··

01-1644-00-Ma

9 ·

9 «

9 9

9 9 9 ·

9 9 9 • 9 9 · ·· ··

9

Example 21

N- [4- [2- [N-Methyl-N- [2- (2-chlorophenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrogen fumarate

The title compound was prepared according to the procedure in Example 19, except that N- [2- (2-chloro-phenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) -acetamide was used as the starting material (Example 52). In this way the fumarate salt was obtained in 46% yield, m.p. 152153 ° C.

^X HMR (DMSO-d): 1.12 (d, 3H, _C-CH3); 2.40 (s, 3H, NCH ₃ ); 2, 60-2, 90 (m, 4H, _{N-CH2 -CH2} -kr); 2.92 (s, 3H, _s-CH3); 3.24 (m, 1H, CH ₂ -CJÍ-N); 3.96 (dd, J = 10.0 and 6.0 Hz, 1H) and 4.10 (dd, J = 10.0 and 5.6 Hz, 1H) (O-CH2-CH); 6.60 (s, 2H, fumaric acid); 6.90-7.45 (m, 7H, Ar); 9.58 (s, 1H, ArNH-S).

Example 22

N- [4- [2- [N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

Mixture containing 0.58 g (2.08 mmol) of 2- (2,6-dimethylphenoxy) -1-methylethylamine (US 3,659,019) and 0.3 g (1.08 mmol) of N [4- (2-bromoethyl) phenyl ] methanesulfonamide (GB 971.041) was melted at 120 ° C for 4 hours. The mixture is purified by column chromatography using a 9: 0.2 mixture of dichloromethane and methanol as eluent. The product was triturated with hexane and filtered to give the base as white crystals in 64% yield, m.p. Mp 81-84 ° C.

01-1644-00-Ma · · J JJ J J í; ; . . . · · ··· · »· ·. ........ ·.

* ¹ H NMR (CDCl ₃ ): 1.14 (d, 3H, C-CH ₃ ); 2.18 (s, 6H, _ArCH3); 2.86 (s, 3H, _S-CH3); 2.70-3.20 (m, 5H, CH ₂ -CN-N-CH ₂ Cl ₂ -Ar); 3.64 (d, 2H, 0-CH ₂ -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 was obtained as white crystals in 60% yield, m.p. 210-211 ° C.

Example 23

N- [4- [2- [N-Methyl-N- [3- (2,6-dimethylphenoxy) propyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared as described in Example 22, except that N-methyl-3- (2,6-dimethylphenoxy) propylamine (BE 626.725) was used as the starting material. An oil base is obtained in 59% yield.

¹ H NMR (CDCl ₃ , bases): 1.96 (m, 2H, CH ₂ -C ₁ H ₂ -CH ₂ ); 2.26 (s, 6H, _Ar-CH3); 2.35 (s, 3H, N-CH _3); 2.58 to 3.82 (m, 6H, CH ₂ -CH ₂ -N-CN ₂ -CN ₂ -Ar); 2.92 (s, 3H, _S-CH3); 3.75 (t, 2H, OC / I ₂ -CH _2); 6.00-6.60 (1 H, NH); 6.82-7.02 (m, 3H, dimethyl-phenoxy); 7.16 (s, 4H, 4-methanesulfonamidorenyl).

The hydrochloride salt was obtained as white crystals in 49% yield, m.p. 115-117 [deg.] C.

9 99 • 99

9 9

9 9

99

01-1644-00-Ma

9 ·

9 «

9 9

9

9

9 9

99

Example 24

N- [4- [2- [N-Methyl-N- [4- (2,6-dimethylphenoxy) butyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared according to the procedure in Example 22, except that N-methyl-4- (2,6-dimethyl-phenoxy) -butylamine (BE 626.725) was used as the starting material. An oil base is obtained in 57% yield.

¹ H NMR (CDCl ₃ , bases): 1.62-1, 88 (m, 4H, CH 2 -CH 2 -C / 12-CH 2);

2.26 (s, 6H, _Ar-CH3); 2.32 (s, 3H, N-CH _3); 2.45-2.85 (m,

6H, CH ₂ -C ₁₂ -N-CH ₂ -C 12 -Ar); 2.95 (s, 3H, _S-CH3); 3.75 (t, 2H, O-OT 2 -CH 2); 5.30-6.30 (1H, NH); 6.82-7.02 (m, 3H, dimethyleneoxy); 7.16 (s, 4H, 4-methanesulfonamidorenyl).

The hydrochloride salt is obtained in the form of strongly hygroscopic, not completely white crystals, in 42% yield.

Example 25

N- [4- [2- [N-Methyl-N- [4- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] 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 with stirring 0.11 mL (0.768 mmol) of triethylamine followed by 0.082 mL (7.04 mmol) of benzoyl chloride. The reaction mixture is stirred at room temperature (cooled or warmed if necessary). After completion of the reaction, the reaction mixture was degassed

01-1644-00-Ma by evaporation under reduced pressure and 10 ml of water are added to the evaporation residue and, if necessary, the alkaline pH is adjusted by adding sodium hydroxide solution. The product was extracted three times with 20 ml of ethyl acetate each time. The organic phase is washed with 50 ml of water, dried and evaporated to give 0.24 g (90% yield) of an oil.

¹ H NMR (CDCl ₃ ): 1.16 (d, 3H, C-CH ₃ ); 2.25 (s, 6H, _ArCH3); 2.45 (s, 3H, N-CH _3); 2.65-2.85 (m, 4H, _{N-CH2 -CH2} -Ar); 3.26 (sx, 1H, CH ₂ -CH-N); 3.64 (dd, J = 9.5 and 6.1 Hz, 1H) and 3.84 (dd, J = 9.5 and 5.6 Hz, 1H) _{(O-CH2 -CH2);} 6.80-7.00 (m, 3H, Ar); 7.10 (d, 2H) and 7.80 (d, 2H) (p-benzoylaminophenyl); 7.25-7.45 (m, 3H) and 7.56 (d, 2H) benzoyl group); 8.70 (s, 1H, NH).

The hydrochloride salt was obtained as white crystals (0.19 g, 66% yield), m.p. 108-111 ° C.

Example 26

N- [4- [2- [N-Methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] acetamide sesquihydrochloride monohydrate

The title compound was prepared as described in Example 25, except that acetyl chloride was used as the acylating agent. The salt is thus obtained in the form of white crystals in 68% yield, m.p. Mp 104-106 ° C.

Analysis for C 2 H ₂ ON _{2 3} 02.1,5HC1. H ₂ O (molecular weight 427.20):

C, 61.85; H, 7.90; N, 6.56; Cl, 12.44; H ₂ O 4.22%;

Found: C, 61.79; H, 7.74; N, 6.34; Cl, 13.96; H ₂ O 4.70%.

Ma-01-1644-00 • · · · · · * · · · · · φ φφ φφ> · «• φ># · · · · φ • φ ·· ·· ·· φφ # ¹ HMR (DMSO- (g): 1.40-1.50 (m, 3,, C-CH ₃ ); 2.05 (s, 3H, Ac); 2.15 (s, 6H, _Ar-CH3); 2.80-2.90 (m, 3H, N-CH _3); 2903.60 (m, 4H, _N-CH2 -Ar -Ctf _2); 3.85 (m, 1H, CH ₂ -CH-N); 4054.15 (m, 2H, 0-CH ₂ -CH); 6.70-7.05 (m, 3H, Ar); 7.15-7.25 (m, 2H) and 7.55-7.65 (m, 2H) (p-acetaminophenyl); 10.15 (s,

1H, Ar-W (t-CO); 11.22 (br. 1H, NH &lt; ⁺ & gt ^; ).

Example 27 1-Methyl-3- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] thiourea sesquihydrochloride, hemihydrate

To a solution containing 0.30 g (0.96 mmol) of N- [2- (2,6-dimethylephenoxy) -1-methylethyl] -N-methyl-2- (4-aminophenyl) ethylamine (Example 9) in 2.5 ml of dioxane was added 0.077 g (1.05 mmol) of methyl isothiocyanate. The reaction mixture is stirred at room temperature (and if necessary warmed or added isothiocyanate). After completion of the reaction, the solvent was evaporated under reduced pressure. The evaporation residue is purified by column chromatography or triturated with a small amount of n-hexane, decanted and 10 ml of water are added to the oil obtained, its pH is adjusted to alkaline by addition of sodium hydroxide solution and then the product is extracted three times, 20 ml each of ethyl acetate. The combined organic phase is washed with 50 ml of water, dried and evaporated to give 0.18 g (48% yield) of an oil base.

^X HMR (CDC1 _3): 1.16 (d, 3H, _C-CH3); 2.26 (s, 6H, _ArCH3); 2.42 (s, 3H, N-CH _3); 2, 65-2,90 (m, 4H, _{N-CH2 -CH2} -Ar); 3.10 (d, 3H, _NH-CH3); 3.25 (m, 1H, CH ₂ -CH-N); 3.62 (dd, J = 9.3 and 6.1 Hz, 1H); a 3.85 (dd, J = 9.3 and 5.9 Hz, 1H) (0-CH ₂ · 9 9 99

9 9 9

9 9 9

99

01-1644-00-Ma

98 • 9 9 9

9 9 9

9 · · *

99

CH); 6.04 (d, CS-WH-CH _3); 6.85-7.00 (m, 3H, Ar); 7.12 (d,

2H) and 7.26 (d, 2H) (p-thioureidophenyl); 8.00 (s, 1H, Ar-WH-CS).

The salt was obtained in a yield of 0.136 g (31%); in the form of hygroscopic white crystals, m.p .: 120-122 ° C.

Analysis for C ₂ H ₃ IN ₃ OS. 1.5HCl 1.0.5H ₂ O (MW 449.27):

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 title compound was prepared as described in Example 27, except that ethyl isocyanate was used as the reagent. An oil base is obtained in 59% yield.

¹ H NMR (CDCl ₃ ): 1.05 (t, 3H, CH ₂ -CH ₃ ); 1.15 (d, 3H, CH -)

CH ₃ ) ; 2, 28 (s, 6H, _Ar-CH3); 2.40 (s, 3H, N-CH _3); 2,60-2,80 (m, 4H, _{N-CH2 -CH2} -Ar); 3, 08-3.28 (m, 3H, N-CH ₂ -CH ₃ and CH ₂ -CÍÍ- N); 3.58 : (dd, J = 9.1 and 6.5 Hz, 1H) and 3.86 (dd, J = 9.1 and 5.8 Hz, 1H) (O-CH 2 -CH); 6.00 (t, 1H, CO-W (CH ₂ ); 6.82-7.02 (m, 3H, o-dimethylenenoxy) ; 7.05 (d, 2H) 7.22 (d,

2H) (p-ethylureidophenyl); 7.90 (s, 1H, Ar - MH - CO).

ftft ftft

01-1644-00-Ma ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Example 29

N- [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -N-methyl-2- [4- (N-ethylamino) -phenyl] -ethylamine

The title compound was prepared according to the procedure in Example 19, except that N- [4- [2- [N-methyl-N- [2- (2,6-dimethyl-phenoxy) -1-methyl-ethyl] amino] -ethyl] was used as the starting material Phenyl] acetamide (Example 26). An oil base is thus obtained in 60% yield.

^X HMR (CDCl, base): 1.17 (d, 3H, CH-CH3); 1.21 (t, 3H, CH 2 -CH 3); 2.30 (s, 6H, _Ar-CH3); 2.42 (s, 3H, N-CH _3); 2602.80 (m, 4H, _{N-CH2 -CH2} -Ar); 3.11 (q, 2H, N-CH ₂ -CH _3); 3.01

(m, 1H, CH ₂ -CH-N); 3.59 (dd, J = 9.1 and 6.7 Hz, 1H) and 3.86 (dd, J = 9.1 and 5.6 Hz, 1H) (O-CH 2 -CH); 6.54 (d, 2H) and 3.86 (dd, J = 9.1 and 5.6 Hz, 1H) (O-CH 2 -CH); 6.54 (d, 2H) and 7.01 (d, 2H) (p-ethylaminophenyl); 6, 86-7, 06 / (m, 3H,

o-dimethylphenoxy).

Example 30

N- [4- [2- [N-Propyl-N- [2- (2,6-dimethylphenoxy) ethyl] amino] ethyl] phenyl] methanesulfonamide

The title compound was prepared as described in Example 22, except that N- [2- (2,6-dimethylphenoxy) ethyl] propylamine (EP 152,131) was used as the starting material. An oil base is thus obtained in 25% yield.

¹ H NMR (CDCl 3, bases): 0.88 (t, 3H, N-CH 2 -CH 2 -CH 3); 1.52 (m, 2H, N-CH 2 -CH 2 -CH 3); 2.27 (s, 6H, _Ar-CH3); 2.60 (t, 2 H,

4 44

4 4

4 4 44

4 4 <

4 4 <

44

01-1644-00-Ma 4 4 44 44

N-CH ₂ -CH ₂ -CH ₃ ); 2.70-2.90 (m, 4H, _{N-CH2 -CH2} -Ar); 2.95 (s,

3H, _S-CH3); 2.99 (t, 2H, _{O-CH2 -CH2} -N); 3.85 (t, 2H, _{O-CH2 CH2} -N); 6.85-7.05 (m, 3H, 2,6-dimethylphenoxy); 7.16 (s, 4H, p-methanesulfonamidophenyl).

Example 31

N- [4- [2- [N-Methyl-N- [2- (2-isopropylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide hydrochloride

The title compound was prepared according to the procedure in Example 22, except that N-methyl-2- (2-isopropyl-phenoxy) -1-methylethylamine was used as the starting material (Example 49). An oil base was prepared in 52% yield.

¹ H NMR (CDCl ₃ , bases): 1.12-1.22 (m, 9H, C ₁ -C ₃ and Ar-CH (CH ₃ ) ₂ ); 2.41 (s, 3H, N-CH _3); 2.70-2.80 (m, 4H, _{N-CH2 -CH2} -Ar); 3.15-3.40 (m, 2H, CH ₂ -CH-N and Cr-CH- _{(CH3) 2);} 3.81 (dd, J = 9.3 and 6.4 · Ηζ, 1H) and 4.00 (dd, J = 9.3 and 5.4 Hz, 1H) (0CH ₂ CH); 6.77 (dd, J = 8.0 and 1.0 Hz, 1H); 6.92 (td, J = 7.5 and 1.0 Hz, 1H); 7.10-7.25 (m, 6H) (Ar).

The hydrochloride salt was obtained in a total yield of 38%; as white crystals, m.p. M.p. 86-89 ° C.

01-1644-00-Ma 4 9 4 4

44 4 4 4 4

4 4 4

4 4 4

4 4 4

4 4 4

4 4 4

Preparation of starting materials

Example 32

4- (Methanesulfonamido) phenylacetic acid

In a solution containing 5.44 g (53 mmol) of sodium carbonate in 36 ml of water, dissolve 3.2 g (20 mmol) of 4-aminophenylacetic acid and add 1.7 ml (2.48 g, 22 mmol) in one portion. of methanesulfonyl chloride and the mixture was heated at 85 ° C for 4 hours. After cooling and acidification to pH 3 with concentrated hydrochloric acid, the mixture was allowed to cool overnight in the refrigerator, filtered, rinsed with water and dried to give 2.7 g of crude product which was recrystallized from 6 ml of hot water to give 2.40 g of the title compound. in the form of beige laminar crystals (53% yield), mp 145-147 [deg.] C.

^X HMR (DMSO- d): 2.95 (s, 3H, _S-CH3); 3.48 (s, 2H, ArCH ₂ -CO); 7.10 (d, 2H) and 7.18 (d, 2H) (Ar); 9.65 (br. 1H, NH); 12.25 (br, 1H, COOH).

Preparation of Compounds of Formula V

Example 33

1- (2,5-Dimethylphenoxy) -2-propanol

To a solution containing 3.67 g (30 mmol) of 2,5-dimethylphenol in 16 ml of 96% ethanol solution was added 2.61 g (45 mmol) of propylene oxide and 0.44 g (3.2 mmol) of potassium carbonate, and the resulting suspension was then cook with stirring for 6 hours. After filtering the reaction mixture and washing with ethanol, it is evaporated under reduced pressure

01-1644-00-Ma ftft ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft · ft ft ft ft ft ft · Ftftftft ftft ·· ·· solvent. The crude product (obtained in 100% yield) is purified by distillation under reduced pressure. 85% of a colorless liquid having a boiling point of 104107 ° C / 0.26 KPa are obtained; RF = 0.1 (toluene).

Example 34 (R) -1- (2,6-Dimethyl-phenoxy) -2-propanol

The title compound was prepared according to the procedure in Example 33, except that 2,6-dimethylphenol and R (+) propylene oxide were used as starting materials to give the crude product in 100% yield. Chiral HPLC analysis (Chiralcel OJ column) showed that the product showed 74.4% chemical purity without S-enantiomer content.

Example 35 (S) -1- (2,6-Dimethyl-phenoxy) -2-propanol

The title compound was prepared as described in Example 33 except that 2,6-dimethylphenol and S (-) propylene oxide were used as starting materials to provide the crude product in 100% yield. Chiral HPLC analysis (Chiralcel OJ column) showed that the product showed 78% chemical purity without R-enantiomer content.

01-1644-00-Ma »

0 · 99

9 9

9,494 • 9,9 1

0 0 «

44 • 3 • · 0 0 0 ·

Example 36

1- (2-Isopropylphenoxy) -2-propanol

The title compound was prepared according to the procedure in Example 33, except that 2-isopropylphenol and propylene oxide were used as starting materials to give the crude product in 100% yield; Rf = 0.1 (toluene).

Preparation of Compounds of Formula IV

General method

To a solution of 30 mmol of a compound of formula V in 10 mL of pyridine was added 7.63 g (40 mmol) of 4-toluenesulfonyl chloride while stirring at room temperature. After stirring for 3 hours, the reaction mixture was poured into 55 ml of water. The product is extracted twice with 40 ml of ethyl acetate each time, the organic phase is washed twice with 25 ml of 2N hydrochloric acid each, twice with 20 ml of water, twice with 20 ml of 1N sodium carbonate solution and finally with three times with 20 ml of water each. If necessary, the solvent is removed by evaporation and the evaporation residue is crystallized from a mixture of hexane and diisopropyl ether.

Using the general method described above, the following compounds of formula IV were prepared

R ¹ '3

_Λ »Λ-O-CH₂-CH fCHVfCH-X (IV) wherein R ^1, R ² and R ³ are as defined in Table 10, Nam is 0 and X means 4-toluenesulfonyloxy.

• φ

01-1644-00-Ma

τ4 (ϋ

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Η α

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Other ^_D20 = +33, 8 ° (c = 1, methanol) ^_D20 = -33.8 ° (c = 1, methanol) 4J a • 0 -p 58-59 71-72 78-80 O what 1 WHAT r- ~ 51-62 long- good 36-37 Yield (%) O what O what ’ΧΓ <o <0 cn r- cn CN Starting material 1- (2,5-Dimethylphenoxy) -2-propanol (Example 33) 1 CN 1 ►> 1 X O β φ ra or h 1 — i O> 1 β + J φ 0 ε p -5 o. Q 1 cn CN 1 rH (R) -1- (2,6-Dimethylphenoxy) 2-propanol (Example 34) (S) -1- (2,6-Dimethylphenoxy) 2-propanol (Example 35) 1 CN 1 > 1 X Ο β β φ Ο m β - ι nj>, d χ: ο +> Φ d WITH 1 CN 1 tH 1- (2-Isopropylphenoxy) -2-propanol (Example 36) 7 * 5 ro. X υ ro X at ro X O 1 X it X at 1 cn (O X O ro X O 7 * 5 (O X O 1 LO n X O 1 cn Γ7 X O 1 CD ro X O 1 what X X 7 * 5 ro X at 1 CN ro X O 1 CN (O X O 1 CN n X O 1 CN ro X at 1 CN i ~ X ro o x 1 o CN Example r ~ cn WHAT cn cn cn O IN rH OJ

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386,347 tl (0 Λ

01-1644-00-Ma ī .. *. íí í *. ’·:

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Preparation of compounds of formula II

General method

The reaction mixture product obtained at 100 ° C in a sealed tube by reacting 30 mmol of appropriately substituted compounds of formula IV (wherein X is halogen or 4-toluenesulfonyloxy) with 60 ml of a 33% solution of methylamine or substituted amine in ethanol, It is allowed to proceed for 5 hours and is freed from the solvent by evaporation. The oil obtained is taken up in 40 ml of 2N aqueous hydrochloric acid solution and washed with 10 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 10 by the addition of 5N sodium hydroxide solution, and the mixture was then extracted three times with 50 ml of dichloromethane each time. The organic phase is washed twice with 40 ml of water each, dried, filtered and concentrated by evaporation. The oil obtained is converted to a salt or purified by distillation under reduced pressure or used further in crude form.

Using the general method described above, the following compounds of formula (II) are prepared in which R ¹ , R ² , R ³ and R ^{6 have the} meanings defined in Table 11 and n are 0.

· · · · · · · · · · · · · · · · · · · · ·

01-1644-00-Ma ···· · · * ·. · · · · · · · · · · · · · · · · · · · ·

Ο ο -μ Η 177-178 hydrobromide salt 146-149 fumarate 1 100-102 hydrochloride salt 187-188 * hydrobromide salt 188-189 ** hydrobromide salt 106-107 hydrobromide salt 81-83 hydrochloride salt Yield (%) 87 base 70 fumarate 65 hydrochloride salt 88 base 84 base 89 base 96 base Starting material 1>, n * o Ό S -g + j 5 £ · -Q <D N 4J ¹ <U CM 1 r — 1 [2- (2,3-Dimethylphenoxy) -1-methylethyl] -4-toluenesulfonate (Example 38) [2- (2,5-Dimethylphenoxy) -1-methylethyl] -4-toluenesulfonate (Example 37) (S) - [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -4-toluenesulfonate (Example 40) (R) - [2- (2,6-Dimethyl-phenoxy) -1-methylethyl] -4-toluenesulfonate (Example 39) [2- (2-Methylphenoxy) -1-methylethyl] -4-toluenesulfonate (Example 41) [2- (2-Isopropylphenoxy) -1-methylethyl] -4-toluenesulfonate (Example 42) <£> d X O n x O d x at d X O d x O d X O d X O Ιύ X n X O d X O 'd and o 'd xč ω o d X O d X O Pi X d X O 1 what d X at 1 m d X at 1 vo d X O 1 vo X X Pi d X O 1 CM d X at 1 CM d X O 1 CM d X and 1 CM d X and 1 CM d X O 1 CM 1 ►Ř d O Λ2 > H Fri WHAT tn Λ VO M · AND r ~ 00 σ> ’ΝΤ

η

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01-1644-00-Ma

Preparation of compounds of formula III

Example 50

N- [2- (2,3-Dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) acetamide

To a solution containing 0.80 g (3.5 mmol) of 4-methanesulfonamidophenylacetic acid (Example 32) in 20 mL of N, N-dimethylformamide (DMF) was added 0.46 mL (0.42 g, 4.2 mmol).

Of 4-methylmorpholine, the mixture is cooled to -10 ° C and 0.65 ml (0.70 g, 5 mmol) of isobutyl chloroformate is added. After 10 minutes, a solution containing 0.68 g (3.5 mmol) of Nmethyl-2- (2,3-dimethylphenoxy) -1-methylethylamine (Example 44) in 3 mL of DMF, pre-cooled to -10 ° C, was added and The pH of the mixture was adjusted to 8.5 with triethylamine. The reaction mixture was stirred at -10 ° C for 1 hour and then at 0 ° C for an additional hour. Then the solvent was evaporated under reduced pressure and the solid residue was brought to alkaline pH by addition of aqueous ammonia solution and partitioned 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 concentrated by evaporation. In this way, 1.13 g of the title compound is obtained in the form of an amorphous substance, which is suitable for use in the next step without further purification. Yield 80%.

¹ H NMR (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-CH _3); 2,85-3, 05 (m, 6H, N-CH ₃ and

5-CH _3); 3.72 to 4.05 (m, 4H, 0-CH ₂ -CH and CH-C0 ₂ -Ar); 4.45 (m) a

5.15 (m) (total 1H, CH ₂ -CH-N); 6.70 (dd, 1H), 6.83 (t, 1H) and 7.05 (dd, 1H) (2,3-dimethylphenoxy); 7.10-7.22 (m,

4H, 4-methanesulfonamidophenyl); 7.50 (s, 1H, ArNH-S).

01-1644-00-Ma

Example 51

N- [2- (2,5-Dimethylphenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) acetamide

To a solution containing 0.52 g (2.7 mmol) of N-methyl-2- (2,5-dimethylphenoxy) -1-methylethylamine (Example 45) in 15 mL of tetrahydrofuran was added 0.63 g (2.7 mmol) of acid.

4-methanesulfonamidophenylacetic acid (Example 32) and 0.63 g (3.05 mmol) of dicyclohexylcarbodiimide and the reaction mixture was stirred at room temperature for 16 hours. After filtering the mixture, the filtrate was concentrated under reduced pressure, and the pale yellowish resin obtained (about 4.5 g) was purified by column chromatography eluting with a mixture of ethyl acetate and hexane. In this way, 0.76 g (70% yield) of the title compound was obtained as an amorphous material.

^X HMR (CDCl): 1.18-1.36 (m, 3H, _C-CH3); 2.10-2.18 (m,

3H), and 2.25-2.35 (m, 3H) (Ar-CH _3); 2.84 to 3.04 (m, 6H, N-CH ₃ and

5-CH _3); 3.66 (s) and 3.80 (s) (total 2H, CO- CH ₂ -Ar); 3854.05 (m, 2H, O-CH ₂ -CH); 4.44 (m) and 5.10 (m) (total 1H,

CH2 ₍ t-N); 6.56-6, 62 (m, 1H), 6.66-6.74 (m, 1H) and 6.96-7.04 (m, 1H) (2,5-dimethylphenoxy); 7.05-7.20 (m, 4H, p-methanesulfonamidophenyl group); 7.50-7.80 (m, 1H, ArNH-S).

01-1644-00-Ma fc fc fc

Example 52

N- [2- (2-Chlorophenoxy) -1-methylethyl] -N-methyl-2- (4-methanesulfonamidophenyl) acetamide

The title compound was prepared as described in Example 50, except that N-methyl-2- (2-chlorophenoxy) -1-methylethylamine (FR, M. 5,912) was used as the starting material. In this way the title compound was prepared as an amorphous material in 68% yield.

^X HMR (CDC1 _3): 1.25-1.40 (m, 3H, _C-CH3); 2.90-3.00 (m) and 3.12 (s) (total 6H, N-CH ₃ and S-CH ₃ ); 3.70 (s), and 3.85-4.20 (m, total 4H, O- CH ₂ -CH and CH-C0 ₂ -Ar); 4.52 (m) and 5.08 (m) (total 1H, CH ₂ -CH-N); 6.88-7.40 (m, 8H, Ar); 7.45-7.60 (m, 1H, Ar - NH - S).

01-1644-00-Ma ^ M «20? 'SÁMLi

Claims (6)

PATENT REQUIREMENTS • 9 9 9 99 9 9 9 9 · 9 9 9 A compound of formula I wherein: R ¹ and R ² independently represent a hydrogen atom, a halogen atom or a C 1 -C 4 alkyl group; R ³ , R ⁴ and R ⁵ independently represent hydrogen or C 1 -C 4 alkyl; R ⁶ represents a hydrogen atom, a C 1 -C 4 alkyl group or a benzyl group; R ⁷ is nitro or amino, optionally monosubstituted C 1 -C 4 alkyl, benzoyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylcarbamoyl, or alkylthiocarbamoyl C 1 -C 4; both n and m are 0 or 1; with the proviso that R ² is other than hydrogen when R ¹ is hydrogen, 01-1644-00-Ma 9 9 99 99 9 9 9 9 9 9 9 9 9 * 99 9 99998 99 9 9 9 9 9 9 99 99 99 99 and their stereoisomers or mixtures of acid addition salts and hydrates, metabolites of all these compounds. stereoisomers, precursors and The compound of claim 1 selected from the group consisting of N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide, (S) -N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide, (R) -N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] phenyl] methanesulfonamide, N- [4- [2- [N-methyl-N- [2- (2-methylphenoxy) ethyl] amino] ethyl] phenyl] methanesulfonamide, N- [4- [2- [N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] amino] ethyl] 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] phenyl] thiourea, 2- [4-aminophenyl] -N-methyl-N- [2- (2,6-dimethylphenoxy) -1-methylethyl] ethylamine and acid addition salts thereof. A pharmaceutical composition comprising, as active ingredient, a compound of the formula I in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 have the} meanings defined in claim 1, or a therapeutically acceptable salt or hydrate thereof in admixture with solvents, diluents, carriers and additives commonly used in the preparation of medicaments. 01-1644-00-Ma ΦΦΦ · · φ · · φ · · · · · · φ φ The compound of claim 1 for use as a medicament. Use of a compound according to claim 1 for the manufacture of a medicament suitable for the treatment of cardiac arrhythmia. 6. A method for treating diseases associated with arrhythmias in a mammal comprising administering an antiarrhythmic effective amount of a compound of claim 1 to a mammal in need thereof.