FR2729142A1 - New heterocyclic amine derivs. - Google Patents

Abstract

Heterocyclic amine derivs. of formula (I) and their salts and solvates are new. J = opt. unsatd. 5- to 7-membered heterocyclic ring contg. one N atom which is substd. by A, B or R4; A, B = a bond; or 1-4C n-alkylene in which each C atom is opt. substd. by a 1-6C alkyl gp.; Z = a bond, CH2, CH2CH2 or XCH2CH2; X = O or S; D = CO, SO2, P(O)ORs or NHCO; Rs = 1-6C alkyl; Q = aryl, aralkyl, aralkenyl or aralkynyl, all opt. ring-substd. by 1-5 of halo, nitro, amino, CN, COOH, alkoxycarbonyl, alkylamido, alkyl-sulphonamido, 1H-imidazolyl, alkyl or alkoxy; opt. benzo-fused furyl, pyranyl, thienyl, thiazolyl, imidazolyl or triazolyl; opt. substd. indolyl, oxo-indolyl, indenyl, indanyl, iso-indenyl, indazolyl, indolizinyl, benzo-furazanyl or pyridyl; or opt. aryl-fused cycloalkyl; R1-R3 = H, 1-6C alkyl, OH or 1-6C alkoxy, or any two of R1-R3 on adjacent C atoms may form a fused heterocyclic ring contg. 4-6 atoms, including 1-3 O or N atoms; Ar = aryl opt. substd. by R1-R3; or opt. substd. heteroaryl; R4 = H, 1-6C alkyl, 2-6C alkenyl or 3-8C cycloalkyl.

Description

 The present invention relates to certain new compounds, to pharmaceutical compositions containing these compounds, to a process for the preparation of these compounds and to the use of these compounds as active therapeutic agents, in particular in the treatment of atrial or ventricular heart arrhythmias.

 Antiarrhythmic agents are classified according to their electrophysiological effects on the heart cell (Vaugham Williams, 1970, 1989): class I agents block rapid sodium current, class II agents are adrenergic blockers, class III agents block potassium currents, class IV agents block calcium current and class V agents are specific sinus node inhibitors.

 A majority of ventricular and atrial arrhythmias are related to a reentry circuit. The lengthening of the refractory period of the myocardium inside or surrounding such a re-entry circuit is a potential mechanism for the management of cardiac arrhythmias.

 As class III antiarrhythmic agents block potassium heart currents, they prolong the repolarization process and increase the refractory period. Consequently, class III agents represent the most specific class for treating re-entry arrhythmias.

 However, due to their mechanism of action, i.e. an increase dependent on the concentration of the duration of the cardiac action potential, higher doses of anti-arrhythmic agents of low grade III can trigger arrhythmias. These arrhythmias, known as torsades de pointes, represent the main harmful effect for all pure class III compounds currently under development.

 It has been discovered that certain new heterocyclic amines induce a self-limiting increase in the duration of the cardiac action potential, linked to a double blockage of the calcium and potassium heart channels. They therefore offer an improved pharmacological profile compared to pure anti-arrhythmic agents of class III and in particular, they have a low pro-arrhythmic potential and quickly restore the contractility of the ischemic myocardium.

ou à un sel de celui-ci ou à un solvate de ceux-ci, dans laquelle:
J représente un noyau hétérocyclique saturé ou insaturé à 5,6 ou 7
chaînons contenant un atome d'azote, cet atome d'azote étant
substitué par l'un des groupes A, B et R4;
A représente une liaison ou un groupe n-alkylène en C14 dans
lequel chaque atome de carbone est éventuellement substitué par
un groupe alkyle en C1-6;
B représente une liaison ou un groupe n-alkylène en C14 dans
lequel chaque atome de carbone est éventuellement substitué par
un groupe alkyle en C1-6;;
D représente un groupe CO, S02, NH-CO ou P(O)ORs, dans lequel Rs
est un groupe allyle en C1-6;
Z représente une liaison, un groupe CH2, (CH2)2 ou X-CH2-CH2
dans lequel X est un atome d'oxygène ou de soufre;
Q représente un groupe aryle, aralkyle, aralcényle ou aralcynyle,
dans lesquels la partie aryle peut ne pas être substituée ou être
substituée avec 1 à 5 substituants choisis parmi un atome
d'halogène, un groupe nitro, amino, cyano, carboxy,
alcoxycarbonyle, alkylamido, alkylsulfonamido, iH-imidazolyle,
alkyle ou alcoxy, ou bien Q représente un groupe substitué ou non
substitué choisi parmi les groupes furanyle, pyranyle, thiényle,
thiazolyle, imidazolyle, triazolyle ou les équivalents condensés avec
un groupe benzo de furanyle, pyranyle, thiényle, thiazolyle,
imidazolyle, ou triazolyle, indolyle, oxoindolyle, indanyle,
indényle, isoindényle, indazolyle, indolizinyle, benzofurazanyle ou
pyridinyle, ou cycloalkyle éventuellement condensé avec un groupe
aryle; Ri, R2 et R3 représentent chacun indépendamment un atome
d'hydrogène, un groupe allyle, hydroxy ou alcoxy, ou, s'ils sont
attachés à des atomes de carbone adjacents, deux quelconques des
R1, R2 et R3 peuvent former avec les atomes de carbone auxquels
ils sont fixés, un noyau hétérocyclique condensé de 4 à 6 atomes
dans lequel un, deux ou trois de ces atomes sont des atomes
d'oxygène ou d'azote; et
Ar représente un groupe aryle substitué ou non substitué, dans lequel
les substituants éventuels sont les R1, R2 et R3 définis plus haut,
ou bien Ar représente un groupe hétéroaryle substitué ou non
substitué; et
R4 représente un atome d'hydrogène ou un groupe alkyle en Cl4,
alcène en C26 ou cycloalkyle en C3-8.Consequently, the present invention relates to a compound of formula (I):

or a salt thereof or a solvate thereof, in which:
J represents a heterocyclic ring saturated or unsaturated at 5,6 or 7
links containing a nitrogen atom, this nitrogen atom being
substituted by one of the groups A, B and R4;
A represents a bond or a C 14 n-alkylene group in
which each carbon atom is optionally substituted with
a C1-6 alkyl group;
B represents a bond or a C 14 n-alkylene group in
which each carbon atom is optionally substituted with
a C1-6 alkyl group;
D represents a group CO, S02, NH-CO or P (O) ORs, in which Rs
is a C1-6 allyl group;
Z represents a bond, a CH2 group, (CH2) 2 or X-CH2-CH2
wherein X is an oxygen or sulfur atom;
Q represents an aryl, aralkyl, aralkenyl or aralkynyl group,
in which the aryl part may not be substituted or be
substituted with 1 to 5 substituents chosen from an atom
halogen, a nitro, amino, cyano, carboxy group,
alkoxycarbonyl, alkylamido, alkylsulfonamido, iH-imidazolyle,
alkyl or alkoxy, or Q represents a substituted or unsubstituted group
substituted chosen from furanyl, pyranyl, thienyl,
thiazolyle, imidazolyle, triazolyle or the equivalent condensed with
a benzo group of furanyl, pyranyl, thienyl, thiazolyl,
imidazolyle, or triazolyle, indolyle, oxoindolyle, indanyl,
indenyl, isoindenyl, indazolyl, indolizinyl, benzofurazanyl or
pyridinyl, or cycloalkyl optionally condensed with a group
aryl; Ri, R2 and R3 each independently represent an atom
hydrogen, an allyl, hydroxy or alkoxy group, or, if they are
attached to adjacent carbon atoms, any two of
R1, R2 and R3 can form with the carbon atoms to which
they are fixed, a condensed heterocyclic nucleus of 4 to 6 atoms
in which one, two or three of these atoms are atoms
oxygen or nitrogen; and
Ar represents a substituted or unsubstituted aryl group, in which
the possible substituents are the R1, R2 and R3 defined above,
or Ar represents a substituted or unsubstituted heteroaryl group
substituted; and
R4 represents a hydrogen atom or a C1-4 alkyl group,
C26 alkene or C3-8 cycloalkyl.

 Suitably, J is a pyrrolidine or piperidine group.

 Suitably, the nitrogen atom in J and the nitrogen atom in the ZN-A part are separated by 3 to 4 carbon atoms.

 In general, when J is a piperidine group, the substituent A or B which is not attached to the nitrogen atom is fixed in position 2 or in position 3 on the ring.

Suitably, B represents a bond, a group
CH2- or - (CH2) 2-.

 Suitably, D represents a CO group.

 Suitably, Q represents a phenyl group, advantageously a substituted phenyl group.

 Suitably, Z represents a bond.

 Suitably, n is 1 or 2.

 An example of a substituent for Q is a nitro group, in particular a 4-niter group.

 Suitably, one or two of the groups R1, R2 or R3 represent an alkoxy group, for example, a methoxy group, the remaining group or groups being a hydrogen atom.

 Suitably, R4 represents a hydrogen atom or a CH3 group.

 The term "allyl" used herein includes straight or branched chain alkyl groups having from 1 to 12, preferably from 1 to 6 carbon atoms and will include such allyl groups when they form part of other groups as groups alkoxy or arylaikyle.

 The term "alkenyl" used herein includes straight or branched chain alkylene groups having 2 to 12, preferably 2 to 6 carbon atoms and one or more double bonds.

 The term "alkynyl" used herein includes straight or branched chain alkynyl groups having 2 to 12, preferably 2 to 6 carbon atoms and one or more double bonds.

 The term "aryl" used herein includes phenyl and naphthyl groups, preferably a phenyl group, and unless otherwise indicated, these groups are optionally substituted with a maximum of five, preferably three groups selected from a halogen atom, the nitre, amino, cyano, carbon, alkoxycarbonyl, aikylamido, aikylsulfonamido, 1H-imidazolyl, aryl or alkoxy groups.

 Suitable heteroaryl groups include the indole, benzofuran, benzofurazane and benzothiophene groups, substituted in the same manner as that described for the aryl group.

 The term "cycloalkyl" used herein includes cycloalkyl carbon carbon bonds of 4 to 7 carbon atoms.

 The term "halogen" used herein includes fluorine, chlorine or bromine atoms.

 The term "cardiac arrhythmia" used herein includes any modification of the normal rhythm of heartbeat, including without limitation, sinus arrhythmia, premature heartbeat, heart block, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.

 The compounds of formula (I) have chiral carbon atoms and therefore exist in more than one stereoisomeric form.

The invention encompasses any of the stereoisomeric forms, including the enantiomers of the compounds of formula (I) and their mixtures, including the racemates. The different stereoisomeric forms can be resolved or separated from each other by conventional methods, or any given isomer can be obtained by conventional stereospecific or asymmetric syntheses.

 Suitable salts of the compounds of formula (I) include pharmaceutically acceptable salts.

 Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with pharmaceutically acceptable mineral acids, such as hydrochloric, hydrobromic, boric, phosphoric, sulfuric acids and pharmaceutically acceptable organic acids, such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methane sulfonic, a-keto-glutaric, glycerophosphoric and i-phosphoric glucose. The preferred acid addition salt is a hydrochloride.

 Pharmaceutically acceptable salts also include quaternary salts. Examples of quaternary salts include these compounds quaternized by compounds such as those of formula RY-T in which Ry is a C1-6 allyl group, C1-6 phenyl-alkyl or C5-7 cycloalkyl and T is a corresponding radical to an anion of an acid. Suitable examples of Ry include methyl, ethyl and n- and isopropyl groups, as well as benzyl and phenethyl groups.

Suitably, T is a halide such as chloride, bromide and iodide.

 Pharmaceutically acceptable salts also include pharmaceutically acceptable N-oxides and the invention therefore encompasses them.

 The compounds of formula (I) and their salts can also form solvates, in particular pharmaceutically acceptable solvates, such as hydrates, and the present invention extends to these and in particular to point-acceptable solvates. pharmaceutical perspective.

 Salts or solvates of compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts or solvates of compounds of formula (I) or compounds of formula (I) themselves, and as such, form an aspect of the present invention.

dans laquelle A, Ar, B, R1, R2, R3, R4 et Z sont tels que définis en relation avec la formule (I), avec un composé de formule (III):
Q-D-L1 (III) dans laquelle Q est tel que défini en relation avec la formule (I) et: (a) pour des composés de formule (I) dans laquelle D est un groupe
CO, CH2CO, S02 ou P(O)ORS, L1 représente un groupe mobile
comme un atome d'halogène; et (b) pour des composés de formule (I) dans laquelle D est un groupe
NH-CO, Q-D-L1 représente le groupe N=C=O; et ensuite, si cela est requis, réalisation d'une ou de plusieurs des étapes éventuelles suivantes: (i) conversion d'un composé de formule (I) en un autre composé de
formule (I); (ii) préparation d'un sel du composé de formule (I) et/ou d'un solvate
de ceux-ci.A compound of formula (I) or a salt thereof, or a solvate thereof, can be prepared by reaction of a compound of formula (II):

in which A, Ar, B, R1, R2, R3, R4 and Z are as defined in relation to formula (I), with a compound of formula (III):
QD-L1 (III) in which Q is as defined in relation to formula (I) and: (a) for compounds of formula (I) in which D is a group
CO, CH2CO, S02 or P (O) ORS, L1 represents a mobile group
as a halogen atom; and (b) for compounds of formula (I) in which D is a group
NH-CO, QD-L1 represents the group N = C = O; and then, if required, carrying out one or more of the following optional steps: (i) conversion of a compound of formula (I) into another compound of
formula (I); (ii) preparation of a salt of the compound of formula (I) and / or of a solvate
of these.

 The reaction conditions used for the reaction between the compound of formula (II) and the compound of formula (III) are conventional conditions appropriate to the nature of the reagent used; in general, however, the reaction can be carried out in an inert solvent, such as methylene chloride, at any suitable temperature providing a suitable rate of formation of the desired product, generally with cooling or at room temperature, conveniently at OOC or room temperature and preferably in the presence of a base such as triethylamine.

dans laquelle A, J, R1, R2, R3, R4 et Z sont tels que définis en relation avec la formule (I) et Rp représente un groupe protégeant l'atome d'azote, avec un composé de formule (V):
L2-B-Ar (V) dans laquelle B et Ar sont tels que définis en relation avec la formule (I) et L2 est un groupe mobile, comme un atome d'halogène, ou de préférence, un groupe mésylate, et ensuite, si cela est désiré, élimination du groupe protecteur Rp.A compound of formula (II) in which the nitrogen atom of the nucleus of J is substituted by the part -B-Ar can be prepared by reaction of a compound of formula (IV):

in which A, J, R1, R2, R3, R4 and Z are as defined in relation to formula (I) and Rp represents a group protecting the nitrogen atom, with a compound of formula (V):
L2-B-Ar (V) in which B and Ar are as defined in relation to formula (I) and L2 is a mobile group, such as a halogen atom, or preferably, a mesylate group, and then, if desired, removal of the protective group Rp.

 The reaction between the compounds of formulas (IV) and (V) can be carried out in any convenient aprotic solvent, such as acetonitrile, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent.

 Suitably Rp is a t-butyloxycarbonyl group (t-BOC), prepared by treating the appropriate substrate with di-t-butyl dicarbonate in an aprotic solvent such as tetrahydrofuran.

 The removal of the protective group Rp is carried out under suitable conventional conditions, for example, when Rp is t-BOC, with trifluoroacetic acid.

dans laquelle J et R4 sont tels que définis dans la formule (I), A1 est une liaison ou un groupe n-alkylène en C 1-3 dans lequel chaque atome de carbone est éventuellement substitué par un groupe aryle en C1-6 et T1 est un groupe -CHO ou une partie -CH2-L3 dans laquelle L3 représente un groupe mobile, comme un atome d'halogène ou un groupe mésylate, avec un composé de formule (VII):

dans laquelle R1, R2, R3 et Z sont tels que définis en relation avec la formule (I), puis réduction de l'imine intermédiaire ainsi formée.The compounds of formula (nr) can be prepared by reaction of a compound of formula CVI):

in which J and R4 are as defined in formula (I), A1 is a bond or a C 1-3 n-alkylene group in which each carbon atom is optionally substituted by a C1-6 and T1 aryl group is a group -CHO or a part -CH2-L3 in which L3 represents a mobile group, such as a halogen atom or a mesylate group, with a compound of formula (VII):

in which R1, R2, R3 and Z are as defined in relation to formula (I), then reduction of the intermediate imine thus formed.

 When T1 is a -CHO group, the reaction between the compounds of formulas (VI) and (VII) can be carried out according to conventional imidation procedures, such as those described in the Journal of Medicinal Chemistry, 1977, 20, 1111.

 When T1 is a group -CH2-L3 as defined above, the reaction between the compounds of formulas (VI) and (VII) can then be carried out according to procedures described above for the reaction between the compounds of formula (IV) and of formula (V).

 The reduction of the intermediate imine can be carried out by conventional procedures, using for example borohydrides, in an appropriate solvent such as ethanol.

The compounds of formula (III) are known compounds or which can be obtained by procedures analogous to those which are used to prepare known compounds, for example as described in Organic Syntheses Coll. Flight. I, page 394 and
Organic Syntheses Coll. Vol III, page 29.

The compounds of formula (V) are known compounds or which can be prepared according to procedures used to prepare known compounds, for example, as described in
Organic Syntheses Coll. Flight. VI, page 56.

 The compounds of formula (VI) are known compounds or which can be prepared according to procedures analogous to those which are used to prepare known compounds, for example, as described in the Journal oforganic Chemistry, 1960, 25, 560 or 1988 , 53, 3513 and the compounds of formula (VI) wherein A1 is a bond are commercially available compounds.

 The compounds of formula (VII) are known compounds or which can be prepared according to procedures analogous to those which are used to prepare known compounds, for example, as described in Chem. Berichte 1957, 90, 2124 and the compounds of formula (VII) in which Z is a bond are commercially available compounds.

dans laquelle Ar, B, J et R4 sont tels que définis en relation avec la formule (I), avec un composé de formule (in):

dans laquelle R1, R2, R3 et Z sont tels que définis en relation avec la formule (I) et A2 est un groupe n-alkylène en C1-3 dans lequel chaque atome de carbone est éventuellement substitué par un groupe alkyle en C1-6, et L3 est un groupe mobile, comme un atome d'halogène, puis réduction de l'amide ainsi formé.A compound of formula (II) in which the nitrogen atom of the nucleus of J is substituted by A can be prepared by reaction of a compound of formula (VIII):

in which Ar, B, J and R4 are as defined in relation to formula (I), with a compound of formula (in):

in which R1, R2, R3 and Z are as defined in relation to formula (I) and A2 is a C1-3 n-alkylene group in which each carbon atom is optionally substituted by a C1-6 alkyl group , and L3 is a mobile group, like a halogen atom, then reduction of the amide thus formed.

 The reaction between the compounds of formulas (Vm) and (z) can be carried out in any convenient aprotic solvent, such as acetonitrile, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent. The reaction is preferably carried out in the presence of a base such as triethylamine.

 The reduction of the amide function thus formed is suitably carried out according to conventional procedures, for example with a reducing agent of mixed hydride type, such as aluminolithic hydride, in an aprotic solvent such as ethanol and according to the methods described in EP 0.233.762.

 When the required group J is a saturated 6-membered heterocyclic ring, it is often convenient to prepare it from the unsaturated 6-membered heterocyclic ring by reduction according to conventional procedures: for example, when the required group J is a piperidine group, it can be prepared during an appropriate step in the synthesis by reduction of a corresponding pyridine derivative, conveniently by catalytic hydrogenation.

The compounds of formula (VIII) are known compounds or they are prepared according to procedures analogous to those which are used to prepare known compounds, for example the compounds of formula (VIII), in which J is a piperidine group,
B is a bond and R4 is a hydrogen atom, are prepared as described in Bull. Soc. Chim. Fr., 1968, 1000.

 The compounds of formula (Ix) are known compounds or they are prepared according to procedures analogous to those which are used to prepare known compounds, for example as described in EP 0.233.762.

 Note that in any of the reactions mentioned above, any reactive group present in the substrate molecule can be protected according to conventional chemical practice.

 Suitable protecting groups in any of the reactions mentioned above are those which are commonly used in the art. The processes for the formation and removal of these protecting groups are the conventional processes suitable for the molecule to be protected.

 As mentioned above, it is stated that the compounds of the invention have useful therapeutic properties. The present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, useful as an active therapeutic substance.

 More particularly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, useful in the treatment and / or prophylaxis of arrhythmia, especially cardiac arrhythmia, such as ventricular arrhythmia and also ischemic arrhythmias.

 A compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof can be administered per se or, preferably, in the form of a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

 Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a carrier pharmaceutically acceptable to them.

 A compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof are normally administered as a unit dose.

 An amount effective to treat the disorders indicated above depends on factors such as the effectiveness of a compound of formula (I), the particular nature of the pharmaceutically acceptable salt thereof or the solvate thereof acceptable from the pharmaceutical point of view which is chosen, the nature and severity of the disorders to be treated and the weight of the memmifre. However, a unit dose normally contains 0.1 to 500 mg, for example, 2 to 50 mg of the compound of the invention. Unit doses are normally administered one or more times a day, for example, 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, so that the total daily dose is in the range, for an adult of 70 kg, from 0.1 to 2500 mg, more generally from 50 to 2000 mg, for example from 10 to 75 mg, i.e. in the range of about 0.002 to 35 mg / lrg / day, more generally from 1 to 30 mg sgl day, for example, from 0.15 to 1 mgllçg / day.

 Within the dosage range indicated above, no toxicological effects are reported for the compounds of the present invention.

 In such treatment, the compound can be administered by any suitable route, for example, orally, parenterally or topically. For such use, the compound is normally used in the form of a pharmaceutical composition in combination with a carrier, diluent and / or pharmaceutical excipient usable in human or veterinary medicine, although the exact form of the composition depends of course on the administration mode.

 The compositions are prepared by mixing and suitable for oral, parenteral or topical administration, and as such can be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, powders to be reconstituted, solutions or suspensions to be injected or to be infused, suppositories and transdermal devices. Orally administrable compositions are preferred, especially shaped oral compositions, since they are more convenient for general use.

 Tablets and capsules for oral administration are generally presented in unit dose, and contain conventional excipients such as binding agents, fillers, diluents, stacking agents, lubricants, disintegrating agents, dyes, aromas and wetting agents.

The tablets can be coated according to methods well known in the art.

 Suitable fillers for use include cellulose, mannitol, lactose, and the like. Suitable disintegrating agents include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

 The solid oral compositions can be prepared by conventional mixing, filling, tableting or the like procedures. Repeated mixing operations can be used to distribute the active agent in compositions employing large amounts of fillers. These operations are of course conventional in the art.

 Oral liquid preparations can be in the form, for example, of elixirs, syrups, emulsions, solutions or suspensions in water or oil, or can be presented as a dry product. reconstitute with water or other suitable vehicle before use. These liquid preparations can contain conventional additives such as suspending agents, for example, sorbitol, a syrup, a methylcellulose, a gelatin, a hydroxyethyl cellulose, a carboxymethyl cellulose, an aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl phydroxybenzoate or sorbic acid, and if desired, coloring agents or conventional perfumes.

 For parenteral administration, liquid unit dosage forms are prepared using the compound of the present invention and a sterile vehicle. Depending on the vehicle and the concentration used, the compound may be in solution or in suspension in the vehicle. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and sterilizing by filtration before introducing these solutions into a suitable vial or ampoule, which is sealed. It is advantageous to also be able to dissolve in the vehicle, adjuvants such as a local anesthetic, a preservative and buffers. To increase the stability, the composition can be frozen after introduction into the flask and the water removed under vacuum.

 Parenteral suspensions are prepared in almost the same way, except that the active compound is suspended in the vehicle instead of being dissolved therein and that the sterilization is done by exposure to ethylene oxide before setting suspension in the sterile vehicle. It is advantageous to include a surfactant or a wetting agent in the composition to facilitate uniform distribution of the active compound.

For topical administration, the composition may be in the form of a transdermal ointment or patch for the systemic distribution of the compound and may be prepared in a conventional manner, for example, as described in conventional textbooks, such as "Dermatological Formulations ", BW Barry (Drugs and the Pharmaceutical Sciences, Dekker) or"Harry's
Cosmeticology "(Leonard Hill Books).

 In addition, these compositions can contain other active agents such as antihypertensive agents and diuretics.

 As is common practice, the compositions are usually accompanied by written or printed instructions for use useful for the medical treatment concerned.

 The term "pharmaceutically acceptable" used herein includes compounds, compositions and components for human and veterinary use, for example, the term "pharmaceutically acceptable salt" includes a pharmaceutically acceptable salt vet view.

 The present invention further provides a method for the treatment and / or prophylaxis of arrhythmia, in particular cardiac arrhythmia such as ventricular arrhythmia, and also ischemic arrhythmias in a human or non-human mammal, which comprises administration to a human or non-human mammal in need thereof, an effective, non-toxic amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof pharmaceutically acceptable.

 The active component can be conveniently administered in the form of a pharmaceutical composition as defined above, and this forms a particular aspect of the present invention.

 In the treatment and / or prophylaxis of arrhythmia and / or ischemic arrhythmia disorders, the compound of general formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate of these acceptable from the pharmaceutical point of view, can be taken in doses as described above, one to six times a day in an amount ranging from 0.01 to 15 mg / kg, for example from 0, 1 mgllrg to 5 mglkg, so that the total daily dose for an adult of 70 kg is generally in the range of 0.7 mg to 6300 mg and more usually about 7 to 2100 mg.

 Similar administration regimens are suitable for the treatment and / or prophylaxis of non-human mammals.

 According to another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof acceptable from the point of view pharmaceutical, for the manufacture of a medicament for the treatment of arrhythmia, in particular of cardiac arrhythmia such as ventricular arrhythmia and also ischemic arrhythmias.

 The following examples further illustrate the present invention without limiting it in any way.

Description 1 3,4-Dimethoxy-N- (3-pyridyl-methylene) benzeneamine

A mixture containing 3-carboxaldehyde pyridine (26.75 g, 0.25 mol) and 3,4-dimethoxybenzeneamine (38 g; 0.25 mol) in ethanol (250 ml) is stirred at room temperature for three hours The reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica (heptane: ethyl acetate 1: 2) led to 45 g (73.9%) of the desired compound in the form of a brown paste.
Proton NMR is compatible with the structure of the expected compound
Description 2
N- (3,4-Dimethoxyphenyl) -3-pyridinemethaneamine

Sodium borohydride (0.228 g, 6 mmol) is added to a solution of 3,4dimethoxy-N- (3-pyridylmethylene) benzeneamine (D1) (1 g, 4 mmol) in 20 ml of ethanol. The reaction mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. 50 ml of water are added to the residue and the mixture is extracted twice with 20 ml of dichloromethane. The organic phase is washed twice with 30 ml of water and then dried over MgSO 4. Purification by chromatography on silica (heptane: ethyl acetate 1: 2) led to 0.89 g (90%) of the desired compound under form of brown crystals.

1H NMR (CDCl3):: = = 3.80 (2s, 6H, 2xOCH3); 4.32 (s, 2H, CH2); 6.12-6.17 (dd, 1H, J = 8.5Hz, r = 2.6Hz, Ar); 6.27 (d, 1H, J '= 2.6 Hz, Ar); 6.73 (d, 1H, J = 8.5 Hz, Ar); 7.3 (m, 1H, pyr.); 7.7 (m, 1H, pyr.); 8.52 (m, 1H, pyr.); 8.63 (d, 1H, J = 1.8Hz, pyr.) Ppm.

Description 3 [(3,4-Dimethoxyphenyl) -3- (pyridinylmethyl)] 2- (2-methylpropyl) carbamate

Di-ten-butyl dicarbonate (4.4 g, 20 mmol) is added to a solution of N43.4-dimethoxyphenyl) -3-pyridinemethaneamine (D2) (2.44 g, 10 nnol) in 50 ml of
THF. The reaction mixture is heated at reflux for 20 hours and then concentrated in vacuo. Purification by flash chromatography on silica (heptane: ethyl acetate 1: 2) gave 3 g (87%) of the desired compound in the form of light brown crystals.

1H NMR (CDCl3): # = 1.42 (s, 9H, 3xCH3); 3.80 (2s, 6H, 2xOCH3); 4.78 (s, 2H,
CH2N); 6.58 (m, 2H, Ar); 6.73 (d, 1H, Ar); 7.29 (m, 1H, pyr.); 7.63 (m, 1H, pyr.); 8.51 (m, 2H, pyr.) Ppm.

Description 4 [(3,4-dimethoxyphenyl) -3- (piperidinylmethyl)] 2- (2-methylpropyl) carbamate

2- (2-Methylpropyl) (D3) carbamate [(3,4-dimethoxyphenyl) -3- (pyridinylmethyl)] (0.5 g, 1.4 mmol) in solution in 10 ml of acetic acid is hydrogenated at 10 bar, at room temperature, in the presence of a catalytic amount of PtO2. After three hours of reduction, the catalyst is removed by filtration and the reaction mixture is concentrated in vacuo leading to 0.5 g (quant) of desired product in the form of pure brown oil by TLC. The proton NMR is compatible with the expected structure.

Description S 2- (3,4-Dimethoxyphenyl) ethyl methanesulfonate
Metanesulfonyl chloride (11.5 g, 100 mmol) is added dropwise (over 30 min) to a mixture of (3,4imethoxy) benzeneethanol (18.2 g; 100 mmol) and triethylamine (10.8 g , 100 mmol) in 300 ml of acetonitrile, so that the internal temperature remains below 40 "C. The reaction mixture is then stirred at room temperature for 18 hours. This mixture is filtered through Celite and the filtrate is concentrated in vacuo. The crude product obtained is dissolved in 200 ml of ethyl acetate, washed twice with 100 ml of water, dried over MgSO 4 and concentrated in vacuo. 22 g of the desired product is isolated and used as what without further purification.

 1H NMR (CDCl3):: 5 = 2.85 (s, 3H, SCH3); 3.00 (t, 2H, J = 7Hz, CH; 3.86 (s, 3H, OCH3); 3.88 (s, 3H, OCH3); 4.40 (t, 2H, J = 7Hz, OCH2) ; 6.75-6.85 (m, 3H, Ar) ppm.

Description 6 [(3,4-dimethoxyphenyl) - [1- [2- (3,4-dimethoxyphenyl) ethyl] -3piperidinyl] methyl] carbamate of [2- (2-methyipropyl) J

A mixture containing [(3,4-dimethoxyphenyl) -3-piperidinylmethyl] carbamate of [2- (2-ntthylpropyl)] (D4) (3.5 g; 10 mmol), of 2- (3,4-dimethoxyphenyl ) ethyl methanesulfonate (D5) (2.6 g; 10 mmol) and K2CO3 (1.38 g; 1 eq.) in 25 ml of acetonitrile, is heated under reflux for 24 hours. The reaction mixture is then concentrated under vacuum. The residue obtained is dissolved in ioe ml of ethyl acetate is washed three times with 100 ml of water The organic phase is dried over
MgS04 and concentrated in vacuo. Purification by flash chromatography on silica (heptane: ethyl acetate 1: 2) leads to 2.1 g (41%) of the desired compound in the form of a pure brown oil by TLC. The proton NMR is compatible with the expected structure.

Description 7
N- (3,4-Dimethoxyphenyl) -1- [2- (3,4-dimethoxyphenyl) ethyl] -3piperidinmethaneamine

A few drops of trifluoroacetic acid are added to a solution of 2- (2-methylpropyl) (3,4-dimethoxyphenyl) - [1- [2- (3,4-dimethoxyphenyl) ethyl] -3 piperidinyl] methyl carbamate (D6 ) (1 g, 2 mmol) in dichloroethane (15 ml). The reaction mixture is brought to reflux for 5 hours then is concentrated in vacuo. The residue is dissolved in methylene chloride and washed successively with 30 ml of a saturated aqueous solution of NaHCO3 and with water (3 x 30 ml). The organic phase is dried over MgSO4 and concentrated under vacuum, leading to 0.4 g (50%) of a light brown oil, used as it is in the next step.

Description 8 1- [2- (3,4-Dimethoxyphenyl) ethyl] -2-piperidineethanol

A mixture containing 2- (3,4-dimethoxyphenyl) ethyl methanesulfonate (D5) (0.6 g; 2.3 mmol), 2-piperidineethanol (0.3 g, 2.3 mmol) and K2CO3 (0 , 35 g, 2.5 mmol) in 20 ml of acetonitrile, is brought to reflux and is stirred for 24 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The crude product obtained is purified by flash chromatography on silica (dichloromethane methanol 9: 1), which leads to 0.3 g of the expected compound.

1H NMR oil (CDCl3): # = 1.35-2.10 (m, 8H, 4 x CH2); 2.55 (m, 1H, CH); 2.70-2.95 (m, 4H, 2 x CH2); 3.00-3.25 (m, 2H, CH2); 3.704.00 (m, 2H, CH2); 3.86 (s, 3H, OCH3); 3.88 (s, 3H, OCH3); 6.65-6.85 (m, 3H, Ar) ppm.

Description 9
N- (3,4-dimethoxyphenyl) -1- [2- (3,4-dimethoxyphenyl) ethyl] -2piperidineethanamine

Methanesulfonyl chloride (0.35 g, 3 mmol) is added dropwise to a mixture stirred at room temperature, containing 1- [2- (3,4-dimethoxyphenyl) ethyl] - 2-p4 eridineXthanol (D8) (0.6 g, 2 mmol) and triethylamine (0.3 g; 3 mmol) in 20 ml of acetonitrile. The reaction mixture is stirred for 30 min and then concentrated in vacuo. The residue is taken up in ethyl ether and is washed successively with water and a saturated NaCL solution. The organic phase which is dried (MgSO4) and concentrated in vacuo, gives 140 mg of an amorphous solid.

A mixture containing this compound (140 mg, 0.37 mmol), 3,4dimethoxybenzeneamine (60 mg, 0.37 mmol) and K2CO3 (55 mg, 0.37 mmol) in acetonitrile (5 ml) is carried at reflux for 7 hours. The reaction mixture is then concentrated under vacuum, taken up in ethyl acetate, washed with water, dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica led to 50 mg of the expected compound.

1H NMR brown paste (CDCl3): 6 = 1.40-2.10 (m, 9H, 4 x CH2 + NH); 2.60-3.35 (m, 7H, 3 x
CH2, CH); 3.75-3.95 (m, 2H, CH2); 3.78 (s, 3H, OCH3); 3.83 (s, 3H, OCH3); 3.84 (s, 3H, OCH3); 3.85 (s, 3H, OCH3); 6.13 (dd, J1 = 2.6Hz, J2 = 8.5Hz, 1H, Ar); 6.26 (d, J = 2.5Hz, 1H, Ar); 6.60-6.85 (m, 4H, Ar) ppm.

Description 10 Methyl 4-Cyano-4- (3,4-dimethoxyphenyl) butyrate

To a stirred solution of 3,4-dimethoxyphenylacetonitrile (8 g, 45 mmol) in 50 ml of 1,4-dioxaune are added a 40% aqueous solution of Nbenzyltrimethylammonium hydroxide (1.3 ml) then dropwise ( so as to stabilize the internal temperature at 20 C) methyl acrylate (4 g, 47 mmol). the reaction mixture is stirred at room temperature for 24 hours. An additional quantity of methyl acrylate (2 g) is then added and the mixture is stirred at room temperature for 2 days. The crude product is diluted with water, extracted with ethyl ether, washed with water, dried (MgSO 4) and concentrated. Purification by flash chromatography on silica (n-heptane: ethyl acetate 1: 1) gave 4.2 g of the desired compound.

Colorless oil 1H NMR (CDCl3): 6 = 2.10-2.35 (m, 2H, CH2); 2.40-2.60 (m, 2H, CH2); 3.70 (s, 3H,
COOCH3); 3.85-3.95 (m, 1H, CH); 3.89 (s, 3H, OCH3); 3.90 (s, 3H, OCH3); 6.80-6.90 (m, 3H, Ar) ppm.

Description 11 5- (3,4-Dimethoxyphenyl) -2-piperidinone

A mixture containing methyl 4-cyano-4- (3,4-dimethoxyphenyl) butyrate (D10) (2.6 g, 10 mmol) and platinum oxide (200 mg) in 20 ml of acetic acid is reacted with hydrogen (20 bar) at 500C for 4 hours. The reaction mixture is taken up in water and extracted with dichloromethane. The organic phase is washed with a saturated aqueous NaCl solution, dried (MgSO4) and concentrated in vacuo. A simple filtration on silica leads to 1 g of the desired compound in the form of white crystals.

pf = 160 C 1H NMR (CDCl3): # = 1.95-2.20 (m, 2H, CH2); 2.45-2.65 (m, 2H, CH2); 3.00 (m, 1H,
CH); 3.30-3.60 (m, 2H, CH2); 3.87 (s, 3H, OCH3); 3.88 (s, 3H, OCH3); 6.57 (m, 1H, ech.D2O, NH); 6.70-6.90 (m, 3H, Ar) ppm.

Description 12 53- (3,4-Dimethoxyphenyl) piperidine

5- (3,4-dimethoxyphenyl) -2-piperidinone (D11) (1.1 g; 4.7 mmol) is added to a suspension of lithium aluminum hydride (0.53 g; 14 mmol ) in 30 ml of anhydrous THF. The reaction mixture is brought to reflux for 3 hours and is then treated successively with 0.5 ml of water, 0.5 ml of a 15% aqueous NaOH solution and 1.5 ml of water. The mineral product formed is removed by filtration and washed with ethyl ether.

The filtrate is concentrated in vacuo and leads to 950 mg of the desired compound.

1H NMR amorphous solid (CDCl3): # = 1.55-2.15 (m, 4H, 2 x CH2, 1H ech D2O, NH); 2.55-2.75 (m, 3H, CH2, CH); 3.05-3.20 (m, 2H, CH2); 3.86 (s, 3H, OCH3); 3.88 (s, 3H, OCH3); 6.70-6.85 (m, 3H, Ar) ppm.

Description 13
N- (3,4-Dimethoxyphenyl) -3- [3- (3,4-dimethoxyphenyl) -1piperidinyl] propanamide

A mixture containing 3- (3,4-dimethoxyphenyl) pipendin (D12) (221 mg, 1 mmol), 3-chloro-N- (3,4-dimethoxyphenyl) poopanamide (853 mg, 3.5 mmol) and triethylaine (455 mg, 4.5 mmol) in 15 ml of acetonitrile, is brought to reflux for 4 hours. The reaction mixture is concentrated in vacuo. The residue is purified by flash chromatography on silica (ethyl acetate then dichloromethane: methanol 9: 1) and leads to 350 mg of the desired product.

1H NMR brown paste (CDCl3); # = 1.50-1.70 (m, 2H, CH2); 1.90-2.15 (m, 2H, CH2); 2.302.50 (m, 2H, CH2); 2.75-2.90 (m, 2H, CH2); 2,953.15 (m, 3H, CH2, CH); 3.25-3.40 (m, 2H, CH2); 3.85 (s, 6H, 2 x OCH3); 3.86 (s, 3H, OCH3); 3.88 (s, 3H, OCH3); 6.70-6.90 (m, 4H, Ar); 6.96 (dd, Jl = 2HzJ2 = 8Hz, 1H, Ar); 7.45 (d, J = 2Hz, 1H, Ar); 10.35 (broad s, 1H ech.D2O, NH) ppm.

Example 1
N- (3,4-dimethoxyphenyl) -N- hydrochloride [1- [2- (3,4-dimethoxyphenyl) ethyl] 3-piperidinyl] methyl] -4-nitrobenzamide

A solution of 4-nitrobenzoyl chloride (0.5 g, 2.7 mmol) in 20 ml of methylene chloride is added dropwise to a mixture of N- (3,4-dimethoxyphenyl) -1 [2- ( 3,4-dimethoxyphenyl) ethyl] piperidinemethaneamine (D7) (1 g; 2.4 ninol) and triethylamine (0.3 g; 3 mmol) in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature for 3 hours, then it is treated with 50 ml of a 1N aqueous NaOH solution. The organic phase is separated, washed successively with saturated NaCl solution, with water and is dried. on MgSO4. After concentration under vacuum 0.8 g of crude product is isolated. Purification by chromatography on silica (dichloromethane: methanol 98: 2) leads to 0.6 g (44%) of the desired product in the form of the free base. This compound is dissolved in 5 ml of methanol and 0.3 ml of a 6N methanolic solution of HCL The mixture is concentrated in vacuo the residue obtained is triturated with ethyl ether leading to 0.35 g of yellow crystals .

mp = 122-123 C.

 1H NMR (DMSO-d6):: # = 1.15-2.35 (3 m wide, 5H, 2xCH2, CH); 2.7s3.15 (m, 4H, 2xCH2); 3.15-3.30 (m, 2H, CH2); 3.48-3.88 (m, 2H, CH2); 3.65-3.80 (4s, 12H, 4xOCH3); 3.75-4.00 (m, 2H, CH2); 6.70-7.00 (m, 6H, Ar); 758 (d, J = 8.6 Hz, 2H, Ar); 8.07 (d, J = 8.6 Hz, 2H, Ar); 10.43 (s, 1H, ech.D20, NH +) ppm.

Example 2
N- (3,4-dimethoxyphenyl) -N- hydrochloride [2- [2- [2- [3,4 (dimethoxyphenyl) ethyl] -1-piperidinyl] ethyl] 4-nitrobenzamide

A mixture of N- (3,4-dimethoxyphenyl) -1- [2- (3,4-dimethoxyphenyl) ethyl] -2piperidineethanamine (D9) (1.6 g; 3.7 mmol), triethylamine (0.6 g, 6 mmol) and 4-nitrobenzoyl chloride (1.0 g, 5.5 mmol) in solution in dichloromethane, is stirred at room temperature for 2.5 hours. The mixture is washed with a saturated aqueous NaCl solution and then dried over MgSO4. After concentration under vacuum, the crude product is purified by flash chromatography on silica (dichoromethane: methanol 9: 1), which leads to 1.5 g of free base which is dissolved in ethyl acetate and treated with a solution. methanolic HCl. After concentration under vacuum, the oily compound is taken up in dichloromethane and triturated with ethyl ether.

1.5 g of the desired product is thus isolated.

1H NMR yellow foam (DMSO-d6): # = 1.40-2.30 (m, 8H, 4xCH2); 2.80-3.05 (m, 2H, CH2); 3.10-4.10 (m, 7H, 3x CH2, CH); 3.64 (s, 6H, 2xOCH3); 3.72 (s, 6H, 2xOCH3); 6.65-7.00 (m, 6H, Ar); 7.58 (d, J = 8.6 Hz, 2H, Ar); 8.09 (d, J = 8.6 Hz, 2H, Ar); 10.40 (wide band, 1H, scale D2O, NH +) ppm.

Example 3
N- (3,4-dimethoxyphenyl) -3- [3 - [(3,4-dimethoxyphenyl) -1- 1piperidinyl] propyl] -4-nitrobenzamide hydrochloride

A suspension containing N- (3,4-dimethoxyphenyl) -3- [3- (3,4-dimethoxyphenyl) -1-piperidinyli propanamide (D13) (1.5 g; 3.5 mmol) and hydride of lithium aluminum (0.6 g, 6 mmol) in 100 ml of anhydrous 1HF, is brought to reflux for 30 min. The reaction mixture is then treated successively with 0.5 ml of water, 0.4 ml of a 15% aqueous NaOH solution and 1.2 ml of water. The mineral product is removed by filtration and is washed with ethyl ether. The filtrate is concentrated under vacuum and the crude product is used without further purification. A mixture containing 1.6 g of the amine previously obtained, triethylamine (0.65 g; 6.5 mmol) and 4 nitrobenzoyl chloride (1.07 g; 5.8 mmol) in 100 nil of dichloromethane, is stirred at room temperature for 30 min, then is washed with water, dried over MgSO4 and concentrated in vacuo. The residue obtained is purified by flash chromatography on silica (dichloromethane: methanol 95: 5 then 97: 3) which leads to 1.1 g of the expected compound in the form of the free base which is treated with a solution of HCl in ethyl ether. The desired compound (1.1 g) is isolated after trituration in ethyl ether.

Solid amorphous yellow.

1H NMR (DMSO-d6): # = 1.55-2.15 (m, 5H); 2.85-3.85 (m, 8H); 3.66 (s, 6H, 2xOCH3); 3.74 (s, 3H, OCH3); 3.77 (s, 3H, OCH3); 3.91 (m, 2H, CH2); 6.65-7.05 (m, 6H, Ar); 7.56 (d ,, J = 8.5 Hz, 2H, Ar); 8.08 (d, J = 8.5 Hz, 2H, Ar); 10.35 (broad s, 1H, ech.D2O, NH) ppm.

Pharmacological data
Methodology
Guinea pigs (weighing 300 to 350 g) are anesthetized by intravenous injection of sodium pentobarbital (60 mg / kg). After thoracotomy, the heart is quickly excised and placed in an oxygenated Tyrode solution. The papillary muscles are taken from the right ventricle. The preparations are then fixed in the silastic base of a 5 ml organ bath and perfused with solution of oxygenated Tyrode, maintained at 37 + 10 ° C.

The modified Tyrode solution (pH 7.35) has the following composition (mM): NaCl 125; KC14.0; 0.5 MgC12; CaC12 1.8; NaHCO3 24;
NaH2PO4 0.9 and glucose 5.5. The solution is brought to equilibrium with a gas mixture of 95% 02/5% C02.

 After a stabilization period of at least one hour, the transmembrane action potentials are recorded with conventional microelectrodes (10 MOhm) connected to an amplifier with high input impedance (BIOLOGIC VF 180). External stimuli are sent to the preparation with bipolar platinum electrodes placed at one end of the muscle. The pulse duration is 1 ms and the amplitude is twice the threshold. The length of the basic cycle is 1000 ms (PULSAR 6i stimulator).

Signals are monitored on a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis.

 The membrane potential at rest (RMP) and the amplitude of the action potential (APA) are measured, as well as the durations of the action potential (APD) at a repolarization of 30, 50 and 90% (APD 30, APD 50 and APD 90, respectively). Recordings are made after 30 minutes of balancing for each concentration. Only information for which the same impaling is maintained during the entire experiment is used for the analysis.

Claims (5)

1. Compound of formula (I):

 or salt thereof or solvate thereof, wherein: J represents a heterocyclic ring saturated or unsaturated at 5, 6 or 7  links containing a nitrogen atom, this nitrogen atom being  substituted by one of the groups A, B and R4; A represents a bond or a C 14 n-alkylene group in  which each carbon atom is optionally substituted with  a Cl-6 allyl group; B represents a bond or a C1-4 n-alkylene group in  which each carbon atom is optionally substituted with  an alkyl group in D represents a group CO, SO2, NH-CO, or P (O) ORs, in which  Rs is a C1-6 alkyl group; Z represents a bond, a CH2 (CH2) 2 or X-CH2-CH2 group  wherein X is an oxygen or sulfur atom; Q represents an aryl, araikyl, aralkenyl or aralkynyl group,  in which the aryl part may not be substituted or be  substituted with 1 to 5 substituents chosen from an atom  halogen, a nitro, amino, cyano, carboxy group,  alkoxycarbonyl, alkylamido, alkylsulfonamido, 1H-imidazolyl,  allyl or alkoxy, or Q represents a substituted or unsubstituted group  substituted chosen from furanyl, pyranyl, thienyl,  thiazolyle, imidazolyle, triazolyle or the equivalent condensed with  a benzo group of fliranyl, pyranyl, thienyl, thiazolyl,  imidazolyle, or triazolyle, indolyle, oxoindolyle, indanyl,  indenyl, isoindenyl, indazolyl, indolizinyl, benzofurazanyl or  pyridinyl, or cycloalkyl optionally condensed with a group  aryl; R1, R2 and R3 each independently represent an atom  hydrogen, alkyl, hydroxy or alkoxy, or, if they are  attached to adjacent carbon atoms, any two of  Ri, R2 and R3 can form with the carbon atoms to which  they are fixed, a condensed heterocyclic nucleus of 4 to 6 atoms  in which one, two or three of these atoms are atoms  oxygen or nitrogen; and Ar represents a substituted or unsubstituted aryl group, in which  the possible substituents are the R1, R2 and R3 defined above,  or Ar represents a substituted or unsubstituted heteroaryl group  substituted; and R4 represents a hydrogen atom or a C1-6 allyl group,  C2-6 alkene or C3-8 cycloalkyl.  2. A process for the preparation of a compound of formula (I) according to claim 1, or a salt thereof, or a solvate thereof, which process is characterized by the reaction of a composed of formula (il):

 in which A, Ar, B, R1, R2, R3, R4 and Z are as defined in relation to formula (I), with a compound of formula (III):  Q-D-L1 (III) in which Q is as defined in relation to formula (I) and: (a) for compounds of formula (I) in which D is a group  CO, CH2CO, S02 or P (O) ORs, L1 represents a mobile group  as a halogen atom; and (b) for compounds of formula (I) in which D is a group  NH-CO, Q-D-L1 represents the group Q-N = C = O; and then, if required, carrying out one or more of the following optional steps: (i) conversion of a compound of formula (I) into another compound of  formula (I); (ii) preparation of a salt of the compound of formula (I) and / or of a solvate  of these.  3. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier pharmaceutical view for these.  4. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, useful as an active therapeutic substance.  5. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, useful in the treatment and / or prophylaxis of arrhythmia.