FR2729145A1 - New heterocyclic amine derivs. - Google Patents

Abstract

Heterocyclic amine derivs. of formula (I) and their salts and solvates are new. J = opt. unsatd. 4- to 7-membered heterocyclic ring contg. an N atom, provided that the N atom is not bonded to a bridgehead C atom and does not form a bridgehead; A = 1-4C n-alkylene in which each C atom is opt. substd. by 1-6C alkyl; B = H or 1-6C alkyl; E, F = a bond, CH2 or CH2CH2; Z = a bond, CH2, CH2CH2 or XCH2CH2; X = O or S; D = CO, SO2 or NHCO; 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. substd., opt. benzo-fused, furyl, pyranyl, thienyl, thiazolyl, imidazolyl or triazolyl; opt. substd. indolyl, oxoindolyl, indenyl, isoindenyl, indazolyl, indolizinyl, benzofurazanyl or pyridyl; or opt. aryl-fused cycloalkyl; R1-R5 = H, 1-6C alkyl, OH or 1-6C alkoxy; or any two of R1-R5 on adjacent C atoms may form a fused heterocyclic ring contg. 5-6 atoms, including 1-3 O or N atoms.

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 flow, class II agents are adrenergic ss-blockers, class III agents block potassium currents, class W 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 depending on the duration concentration of the cardiac action potential, higher doses of class III antiarrhythmic agents can trigger arrhythmias. These arrhythmias, known as torsades de pointes, represent the main harmful effect for all pure class m compounds currently under development.

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

 It has been surprisingly discovered that certain new amine derivatives have a prolongation of the cardiac action potential as anti-arytic agents, in particular in the treatment of ventricular arrhythmias.

ou à un sel de oelui ou à un solvate de ceux-ci, dans laquelle:
J représente un cycle hétérocyclique de 4 à 7 chaînons, saturé ou
insaturé, contenant un atome d'azote, à condition que l'atome
d'azote ne soit pas attaché à un atome de carbone de tête de pont et
ne forme pas une tête de pont;
A représente un groupe n-alkylène en C14 dans lequel chaque atome
de carbone est éventuellement substitué par un groupe allryle en C16;
B représente un atome d'hydrogène ou un groupe allyle en C1-6;
E et F représentent indépendamment une liaison, un groupe -CH2- ou
-CH2CH2-;
D représente un groupe CO, SO2 ou NH-CO;;
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, araikyle, 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, aikylamido, aikylsulfonamido, lH-imidazolyle,
allyle 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 fliranyle, pyranyle, thiényle, thiazolyle,
imidazolyle, ou triazolyle, indolyle, oxoindolyle, indényle,
isoindényle, indazolyle, indolizinyle, benzofurazanyle ou
pyridinyle ou cycloalkyle éventuellement condensé avec un groupe
aryle; Ri, R2, R3, R4 et R5 représentent chacun indépendamment un atome
d'hydrogène, un groupe alkyle, hydroxy ou alcoxy, ou, s'ils sont
attachés à des atomes de carbone adjacents, deux quelconques des
R1, R2, R3, R4 et R5 peuvent former avec les atomes de carbone
auxquels ils sont fixés, un noyau hétérocyclique condensé de cinq à
six atomes dans lequel un, deux ou trois de ces atomes sont des
atomes d'oxygène ou d'azote;
Convenablement, A représente un groupe (CH2)3. Consequently, the present invention relates to a compound of formula (I):

or a salt of it or a solvate thereof, in which:
J represents a heterocyclic ring of 4 to 7 members, saturated or
unsaturated, containing a nitrogen atom, provided that the atom
of nitrogen is not attached to a bridgehead carbon atom and
does not form a bridgehead;
A represents an n-C14 alkylene group in which each atom
carbon is optionally substituted with a C16 allryl group;
B represents a hydrogen atom or a C1-6 allyl group;
E and F independently represent a bond, a group -CH2- or
-CH2CH2-;
D represents a CO, SO2 or NH-CO 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, aikylamido, aikylsulfonamido, 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, fliranyl, pyranyl, thienyl, thiazolyl group,
imidazolyle, or triazolyle, indolyle, oxoindolyle, indényle,
isoindenyl, indazolyl, indolizinyl, benzofurazanyl or
pyridinyl or cycloalkyl optionally condensed with a group
aryl; Ri, R2, R3, R4 and R5 each independently represent an atom
hydrogen, alkyl, hydroxy or alkoxy, or, if they are
attached to adjacent carbon atoms, any two of
R1, R2, R3, R4 and R5 can form with carbon atoms
to which they are attached, a condensed heterocyclic nucleus of five to
six atoms in which one, two or three of these atoms are
oxygen or nitrogen atoms;
Suitably, A represents a group (CH2) 3.

 Suitably, B represents a hydrogen atom.

 Suitably, D represents a CO group.

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

An example of a substituent for Q is a nitro group,
as a 4-nitro group.

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

Suitably, one or two of the groups R4 and R5
represent an alkoxy group, for example, a methoxy group, the
group possibly remaining being a hydrogen atom.

The term "allyle" used here includes groups
straight or branched chain alkyls having from 1 to 12, advantageously
from 1 to 6 carbon atoms and will include such alkyl groups when they form part of other groups such as alkoxy or arylaikyl groups.

 The term "alkenyl" used herein includes straight chain 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 from 2 to 12, preferably from 2 to 6 carbon atoms and one or more triple 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 one manmum of five, preferably three groups selected from a halogen atom, nitro, amino, cyano, carboxy, alkoxycarbonyl, aikylamido, alkylsulfonamido, 1H-imidazolyl, aryl or alkoxy groups.

 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, aglycerophosphoric and glucose-1-phosphoric acids. 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 for example of the formula RY-T in which Ry is a C1-6 alkyl, phenyl-C1-6 alkyl or C7 cycloalkyl group and T is a radical corresponding to a 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 solvates acceptable from the point of view pharmaceutical.

 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, B, E, F, J, Z, R1, R2, R3, R4 et R5 sont tels que définis en relation avec la formule (I), avec un composé de formule (m)
B-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 ou S02, L1 représente COX ou S02X respectivement, dans
lesquels X est un groupe mobile comme un atome d'halogène; et (b) pour des composés de formule (I) dans laquelle D est un groupe
NH-CO, 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) etlou 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, B, E, F, J, Z, R1, R2, R3, R4 and R5 are as defined in relation to formula (I), with a compound of formula (m)
B-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 or S02, L1 represents COX or S02X respectively, in
which X is a mobile group such as a halogen atom; and (b) for compounds of formula (I) in which D is a group
NH-CO, 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 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 0 ° C or at room temperature and preferably in the presence of a base such as triethylamine.

 The compounds of formula (III) are known compounds available industrially or which can be obtained by procedures analogous to those which are used to prepare known compounds, for example, compounds of formula (here) in which L1 represents a group CO -X can be prepared according to procedures described in Organic Syntheses Coll. Flight. I, page 394 and Organic Syntheses Coll. Vol m, page 29; compounds of formula (III) in which L1 represents an SO2-X group can be prepared according to procedures described in Organic Syntheses Coll.

Flight. vm, page 104 and compounds of formula (III) in which L represents a group -N = C = O can be prepared according to procedures described in Organic Syntheses Coll. Flight. III, page 846.

dans laquelle A, B, E, F, J, R4 et R5 sont tels que définis en relation avec la formule (I) et L2 représente un groupe mobile comme un atome d'halogène ou de préférence un groupe mésylate, avec une composé de formule (V):

dans laquelle Z, R1, R2 et R3 sont tels que définis dans la formule (I).The compounds of formula (11) can be prepared by reaction of a compound of formula (IV)

in which A, B, E, F, J, R4 and R5 are as defined in relation to formula (I) and L2 represents a mobile group such as a halogen atom or preferably a mesylate group, with a compound of formula (V):

in which Z, R1, R2 and R3 are as defined in formula (I).

dans laquelle A, B, E, F, J, R4 et R5 sont tels que définis en relation avec la formule (I) avec du chlorure de méthanesulfonyle.The compounds of formula (nr) can be prepared from the compounds of formula (VI):

in which A, B, E, F, J, R4 and R5 are as defined in relation to formula (I) with methanesulfonyl chloride.

 The reaction conditions for reacting the compound of formula (VI) with methanesulfonyl chloride are conventional conditions using a conventional procedure, for example, those described in Organic Syntheses Coll. Vol VI, page 56.

 The compounds of formula (V), in which Z is a bond, are known compounds, available commercially.

 The compounds of formula (V), wherein Z is other than a bond, are known compounds or which can be prepared according to procedures used to prepare known compounds, for example, as described in Chem. Bertcht, 1974, 90, 2124.

 The compounds of formula (VI) are known compounds and can be prepared according to conventional procedures, for example, as described in the Journal of Medicinal Chemistry, 1998, 36, 1053 1068 and 1069 1068.

 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, in particular of 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 mother. 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 / day, more generally from 1 to 30 mgkg (day, for example, from 0.15 to 1 mglkvjour.

 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 Pharmaceutically acceptable wetting agents include sodium lauryl sulfate sodium.

 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 ", BWBarry (Drugs and the Pharmaceutical Sciences, Dekker) or 'Earry'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 d a pharmaceutically acceptable solvate thereof.

 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 thereof ci acceptable from the pharmaceutical point of view, can be taken in doses as described above.

 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.

1 3a, 4,5,9b-Tetrahydro-3- (3-hydroxypropyl) -7,8-dimethoxy-1H-benzo- [e] - indole-2 (3H) one

A volume of 1.7 ml of acetic acid is added dropwise, with stirring, to a solution of 760 mg (2.6 mmol) of 1,2,3,4-tetrahydro-6,7 dimethoy-2- ethyl oxo-1-naphthalene acetate and 976 mg (12.9 mmol) of Samino propanol in 11 ml of a 1/1 mixture of PnIF and methanol, cooled to 0 C. Stirring is continued for 45 min. , then 345 mg (5.2 mmol) of sodium cyanoborohydride are added. The reaction mixture is stirred for 16 hours at room temperature, then it is made basic with the aid of a 15% aqueous sodium hydroxide solution and concentrated to dryness. The residue is taken up in methylene chloride, the organic phase is washed twice with water, dried over
MgSO4, then concentrated to dryness. The residue is purified by chromatography on silica gel and eluted with a 95/5 mixture of methylene chloride / methanol to give 330 mg (42%) of the desired product in the form of a brown oil.

1H NMR (CDCl3): 6 = 1.66-1.87 (m, 3H, CH2 and 0.5xCH2); 2.00-2.18 (m, 1H, 0.5xCH2); 2.28 (s, 1H, exchange with D20, OH); 2.47 (dd, 1H,
J = 8.7Hz J '= 16.8Hz, 0.5sCH2CO); 2.61-2.72 (m, 2H, ArCH2); 2.92 (dd, 1H, J "= 9.3Hz, J '= 16.8Hz, 0.5xCH2CO); 3.26-3.42 (m, 1H, ArCH); 3, ss 3.80 (m, 4H, CH2NCO and CH2O); 3.80-3.95 (m, 1H, CHNCO); 3.86 (s, 6H, 2xCH3O); 6.59 (s, 2H, Ar) ppm.

D-, tioei2 2,3,3a, 4,5,9b-Hexahydro-7,8-dimethoxy-1H-benzo- [e] -indole-3-propanol

 A solution of 320 mg (1.04 mmol) of 3a, 4,5,9b- tetrahydro-3- (3-hydroxypropyl) -7,8-dimethoxy-1H-benzo- [e] -indole- 2 (3H) -one (D1) in 6 ml of anhydrous TBF is added dropwise, with stirring, to a suspension of 450 mg (11.4 mmol) of LiAlH4 in 10 ml of anhydrous TBF at 0 C. The reaction mixture is brought to reflux for 2 hours. The mixture is cooled to 0 C and 0.45 ml of water, then 0.45 ml of 15% aqueous sodium hydroxide and finally 1.35 ml of water are added dropwise. The reaction mixture is filtered through a layer of Celite, then the solvent is concentrated to dryness. The residue is taken up in methylene chloride, the organic phase is washed with water, dried over MgSO4, then concentrated to dryness to give 310 mg (quantitative) of the desired product in the form of a colorless oil.

1H NMR (CDCl3): 8 = 1.2S1.48 (m, 2H, CH2); 1.53-2.10 (m, 4H, 2xCH2); 2.28-2.63 (m, 3H, ArCH2 and ArCH); 2.63-2.84 (m, 2H, CH2N); 2.94 (broadband, 1H, exchange with D20, OH); 3.02-3.18 (m, 1H, CHN); 3.26-3.48 (m, 2H, CH2N); 3.77-3.94 (m, 2H, CH20); 3.84 (s, 6H, 2xCH3O); 6.60 (s, 2H, Ar) ppm.

Description 3 3- [3- [2,3,3a, 4,5-9b-Hexahydro-7,8-dimethoxy-1H-benzo- [e] -indolyl] - propyl] -methane sulfonate

 A solution of 326 mg (2.84 mmol) of methanesulfonyl chloride in 5 ml of methylene chloride is added dropwise, with stirring, to a solution of 800 mg (2.74 mmol) of 2.3, 3a, 4,5,9b-hexahydro-7,8-dimethoxy- H-benzo-le3- indole-3-propanol (D2) and 0.42 ml (3.01 mmol) of triethylamine in 16 ml of chloride methylene, cooled to 0 C. The mixture is then stirred for one hour at room temperature, then diluted with a little methylene chloride. The mixture is washed twice with water, dried over MgSO4, then concentrated to dryness. The residue is purified by chromatography on silica gel and eluted with a 95/5 mixture of methylene chloride / methanol to give 660 mg (66 %) of the desired product in the form of a brown oil.

1H NMR (CDCl3): # = 1.5s1.86 (m, 4H, 2xCH2); 1.88-2.08 (m, 2H,
CH2); 2.23-2.55 (m, 3H, ArCH2 and 0.5xCH2N; 2.62-2.95 (m, 3H, CHN and 0.5xCH2N); 3.01 (s, 3H, CH3SO3); 3, 04-3.17 (m, 1H, ArCH); 3.25-3.38 (m, 1H, CHN); 3.84 (s, 6H, 2xCH30); 4.32 (t, 2H, J = 6 , 3Hz, CH20); 6.59 (s, 1H, Ar); 6.60 (s, 1H, Ar) ppm.

Description 4 2,3,3a, 4,5,9b-Hexahydro-7,8-dimethoxy-N- (3,4-dimethoxyphenyl) -1H- iii- benzo- [e] -indole-3-propanamine

 A mixture of 500 mg (1.35 mmol) of 3- [3- [2,3,3a, 4,5- 9b-hexahydro-7,8-dimethoxy- 1H-benzo [e] -indolyl] propyl] - methanesulfonate (D3), of 221 mg (1.4 mmol) of 3. $ dimethoxybenzeneamine and of 126 mg (1.5 mmol) of sodium acid carbonate in 15 ml of ethanol, is stirred and brought to reflux for 1, 5 o'clock. The reaction mixture is concentrated to dryness and the residue is taken up in water. The aqueous phase is extracted with methylene chloride and the organic phase is decanted, washed with water, dried over MgSO4, then concentrated to dryness. The residue is purified by chromatography on silica gel and eluted with a 95/5 mixture. methylene chloride / methanol to give 400 mg (69%) of the desired product as an orange oil.

1H NMR (CDCl3): # = 1.51-2.16 (m, 5H, 2xCH2 and 0.5xCH2); 2.25-2.86 (m, 5H, ArCH2, CH2N and 0.5xCH2); 2.83.52 (m, 6H, ArCH, CHN and 2xCH2N); 3.78, 3.80, 3.84 and 3.85 (4s, 12H, 4xCH30); 6.06 (dd, 1H,
J '= 2.4Hz J = 8.6Hz, Ar); 6.15 (s, 1H, Ar); 6.57 (s, 1H, Ar); 6.62 (s, 1H, Ar); 6.72 (d, 1H, J = 8.6Hz, Ar) ppm.

Di5 1,2,5,6-Tetrahydro-8,9-dimethoxy-benzo- [f] -quinoline-3 (4H) -one

1.5 g (7.3 mmol) of 3,4-dihydro-6,7-dimethoxy-2 (1H) -naphthalene-one and 10 mg of Smethylbenzene sulfonic acid in 10 ml of methylbenzene are heated at reflux, then added with 0.78 ml (9.3 mmol) of pyrrolidine in 1 ml of 4-methylbenzene. The mixture is heated at reflux in a device
Dean Stark. When water no longer releases azeotropically, the solvent is concentrated in vacuo. 1.93 g (27.1 mmol) of 2-propenamide is added to the stirred oil and the resulting mixture is heated at 90 ° C. for 2.5 hours, then at 1300 ° C. for 0.5 hour. The reaction mixture is then diluted with 10 ml of hot water and then acidified with concentrated aqueous HCl. The resulting precipitate is filtered and triturated twice with diethyl ether, then with 10 ml of 2-propanone to provide 1.15 g (61%) of the desired compound in the form of beige crystals. Pf = 268-70 C.

1H NMR (DMSO-d6): 6: 2.24 (t, 2H, J = 7.7 Hz, CH20); 2.39-2.74 (m, 6H, 3xCH2); 3.71 and 3.73 (2s, 6H, 2xCH30); 6.69 and 6.76 (2s, 2H, Ar), 9.33 (s, 1H, sample with D2O, NH +) ppm.

1) -nime 4-Benzyl-1,2,5,6-tetrahydro-8,9-dimethoxy-benzo- [f] -quinoline-3 (4H)
one

 A mixture of 1.15 g (4.4 mmol) of 1,2,5,6-tetrahydrt 8,9-dimethoxy-benzo- [f] -quinoline-3 (4H) -one (D5) and 232 mg (5.7 mmol) of 60% sodium hydride in oil, in 23 ml of 1,2-dimethoxyethane, is stirred and heated under reflux for 3 hours.

The mixture is cooled to ambient temperature, then 0.614 ml (5.05 mmol) of benzyl bromide in 3 ml of 1,2-dimethoxyethane is added and the mixture is stirred and heated at reflux for 3 hours. After cooling again to room temperature, the reaction mixture is quenched with 0.65 ml of ethanol and concentrated in vacuo. The residue is taken up in 70 ml of methylene chloride; this solution is washed three times with water, dried over
MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a 98/2 mixture of methylene chloride and methanol as eluent, to provide 1.11 g (72%) of the desired compound in the form of yellow crystals.

Pf. = 11s111 C.

1H NMR (CDCl3): 6: 2.25-2.45 (m, 2H, CH2); 2.60-2.90 (m, 6H, 3xCH2); 3.85 and 3.88 (25.6H, 2xCH3O); 4.97 (d, 2H, NCH2); 6.65 and 6.70 (25.2H, Ar); 7.10-7.40 (m 5H, Ar) ppm.

D - 7 4-Benzyl-1,2,3,4,5,6-hexahydro-8,9-dimethoxy-benzo- [f] -quinoline

 1.1 g (3.14 mmol) of 4-benzyl-1,2,5,6-tetrahydro-8, Gdimethoy-benzo- [f] uinoline-3 (4HWone (D6) in 10 ml of THF is added dropwise to a stirred suspension of 132 mg (3.3 mmol) of aluminolithic hydride in 7 ml of THF The resulting mixture is heated at reflux for 5.5 hours, then cooled and quenched with 0, 13 ml of water, 0.13 ml of 15% aqueous sodium hydroxide, then with 0.4 ml of water The precipitate is separated by filtration and the filtrate is concentrated in vacuo The residue is taken up in water and extracted twice in diethyl ether. The organic solutions are mixed, dried over MgSO4, concentrated in vacuo and the residue is used in the next step without purification.

1) -ni-is 4-Benzyl-1,2,3,4,4a, 5,6,10b-octahydro-8,9-dimethoxy-benzo- [f] - quinoline

A quantity of 298 mg of sodium cyanoborohydride is added little by little to a solution of 660 mg (3.14 mmol) of 4benzyl-1,2,3,4,5,6-hexahydro-8,9-dimethoxy -benzo- [f] -crudequinoline (D7) in 9 ml of acetonitrile. Glacial acetic acid (4 to 5 drops) is added to reach a pH of 6 to 7 and the mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched by addition of 0.8 ml of concentrated aqueous hydrochloric acid and the resulting mixture is concentrated in vacuo. The residue is taken up in 25 ml of water, supplemented with 1.6 ml of 15% aqueous sodium hydroxide and the resulting mixture is extracted twice in methylene chloride. The combined extracts are dried over
MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a 96/4 mixture of methylene chloride and methanol as eluent, to provide an oil which crystallizes from methanol to give 442 mg (66.5%) of the desired compound in the form white crystals.

 P. = 1170C.

1H NMR (CDCl3): #: 1.50-2.20 (m, 6H, 3xCH2); 2.35-3.30 (m, 6H,
CH2N, CH2Ar, CHN and CHAr); 3.82 and 3.84 (25.6H, 2xCH3O); 2.86 (s, 2H, NCH2Ar); 6.52 and 6.59 (2s, 2H, Ar); 7.15-7.60 (m 5H, Ar) ppm.

Description 9 1,2,3,4,4a, 5,6,10b-Octahydro-8,9-dimethoxy-benzo- [f] -quinoline

 720 mg (2.13 mmol) of 4-benzyl1,2,3,4,4a, 5,6,10b-octahydro-8,9-dimethoxy-benzo- [f] -quinoline crude (D8) in 60 ml of methanol is hydrogenated on 200 mg of 10% palladium on charcoal at 25 ° C. and under a pressure of 10 bars. The catalyst is filtered off and the solvent is concentrated in vacuo to provide 453 mg (85%) of a desired compound as a colorless oil.

1H NMR (CDCl3): 6: 1.55-2.30 (m, 6H, 3xCH2); 2.35-3.10 (m, 5H,
CH2N, CH2Ar and CHAr); 3.70 and 3.80 (m, 1H, CHN); 3.83-3.84 (25.6H, 2xCH30); 6.50 and 6.60 (wide band, 2H, Ar) ppm.

D-> eeeiio 1,2,3,4,4a, 5,6,10b-Octahydro-8,9-dimethoxy-N- (3,4-dimethoxyphenyl) -

An amount of 0.45 g (1.82 mmol) of 1,2,3,4,4a, 5,6,10b-octahydro-8,9-dimethoxy-benzo- [f] -quinoline crude (D9), 1.55 g (6.3 mmol) of 3-chloro-N-3,4-dimethoxyphenyl-propanamide and 1.10 g (10.9 mmol) of triethylamine in 12 ml of acetonitrile are stirred and heated under reflux for 16 hours. The solvent is concentrated in vacuo and the residue obtained is taken up in water. The aqueous mixture is made basic by adding 35% aqueous sodium hydroxide, then extracted twice with 50 ml of methylene chloride. The organic solutions are mixed, washed with water, dried over
MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with ethyl acetate, then a 95/5 mixture of methylene chloride and methanol as eluents, to provide 351 mg (43%) of the desired compound as a yellow oil.

 1H NMR (CDCl3):: #: 1.50-2.30 (m, 6H, 3xCH2); 2.2S3.20 (m, 9H, 4xCH2 and CHAr); 3.75 and 4.00 (m, 12H, CH3O); 6.45-6.85 (m, 4H, Ar); 7.46-7.60 (m, 1H, Ar); 10.45-10.85 (wide band, 1H, sample by D2O, NH) ppm.

Description 11 1,2,3,4,4a, 5,6,10b-Octahydro-8,9-dimethoxy-N- (3,4-dimethoxyphenyl) - benzo- [f] -quinoline-4-propanamine

 350 mg (0.77 mmol) of 1,2,3,4,4a, 5,6,10b- octahydro-8,9-dimethoy-benzo- [f] -quinoline-4-propanalnide (D10) in 5 ml of anhydrous THF is added to a stirred suspension of 277 mg (7 mmol) of aluminolithic hydride in 6 ml of THF. The resulting mixture is stirred and heated to reflux for 3 hours, then cooled and quenched with 0.28 ml of water, 0.28 ml of 15% aqueous sodium hydroxide, then with 0.9 ml of water. The precipitate is separated by filtration and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel with a 95/5 mixture of methylene chloride and methanol as eluent to give 277 mg (34%) of the desired compound form of an orange oil.

 1H NMR (CDCl3): #: 1.45-2.20 (m, 8H, 4xCH2); 2.253.40 (m, 10H, 4xCH2 and 2CH); 3.75-3.90 (m, 12H, 4xCH30); 6.10-6.95 (m, 4H, Ar) ppm.

Description 12 1,2,3,4,4a, 5,10,10a-Octahydro-7,8-dimethoxy-N- (3,4-dimethoxyphenyl) -
benzo- [g] -quinoline-4-propanamide

 An amount of 500 mg (1.4 mmole) of 1,2,3,4,4a, 5,6,10,10a-octahydro-7,8-dimethoxy-benzo- [g) -quinoline and 1.72 g (7.07 mmol) of 3-chloro-N-3,4-dimethoxyphenyl-propanamide are treated according to the procedure described in description 10 to provide 653 mg (77.2%) of the desired compound in the form of a brown foam.

1H NMR (DMSO-d6): 6: 1.20-1.90 (m, 4H, 2xCH2); 2.10-3.50 (m, 12H, 5xCH2, CHN and CH); 3.55 and 3.75 (m, 12H, 4xCH30); 6.62 and 6.69 (25.2H,
Ar), 6.80-6.95 (m, 1H, Ar); 7.00-7.10 (m, 1H, Ar); 7.20-7.35 (m, 1H, Ar); 9.85-10.5 (2s, 1H, sample by D2O, NH) ppm.

Description 13 1,2,3,4,4a, 5,10,10a-Octahydro-7,8-dimethoxy-N- (3,4-dimethoxyphenyl) -
benzo- [g] -quinoline-4-propanamine

 An amount of 500 mg (1.1 mmol) of 1,2,3,4,4a, 5,10,10a-octahydro-7,8-dimethoxy-benzo- [g] -quinoline-4-propanamide (D12) and 417 mg (11 mmol) of aluminolithic hydride are treated according to the procedure described in description 11 to provide 400 mg (82.54%) of the desired compound in the form of a light brown oil.

H NMR (DMSO-d6): #: 1.00-1.95 (m, 6H, 3xCH2); 2.00-3.45 (m, 12H, 5xCH2, CHN and CH); 3.55 and 3.80 (m, 12H, 4xCH30); 5.954.05 (m, 1H,
Ar); 6.20-6.35 (m, 1H, Ar); 6.55-6.75 (m, 3H, Ar) ppm.

EXAMPLE 1 N- [3- [3- (2,3,3a, 4,5,9b-hexahydro-7,8-dimethoxy-1H-benzo- [e] -indolyl)] mono-hydrochloride monohydrate - (3,4-dimethoxyphenyl) - 4-nitrobenzamide

 120 mg (0.60 mmol) of nitrobenzoyl chloride is added dropwise to a solution of 250 mg (0.57 mmol) of 2,3,3a, 4,5,9b-hexahydro- 7,8-dimethoxy-N- (3,4- dimethoxyphenylplH-benzo- [e] -indole-3-propanamine (D4) and 0.088 ml (0.627 mmol) of triethylamine in 15 ml of methylene chloride, cooled to 0 C and the mixture is stirred. Stirring is continued for 16 hours at room temperature and 15 ml of methylene chloride are added. The reaction mixture is washed with water, dried over MgSO4 and concentrated to dryness. The residue is purified by chromatography on silica gel with a 95/5 mixture of methylene chloride and methanol as eluent to obtain 290 mg of yellow oil The compound is taken up in methanol and salified by addition of a solution of anhydrous HCl in methyl ether. The solvents are concentrated and the residue is triturated in diethyl ether to give 296 mg (8 2%) of the desired compound as a yellow solid.

1H NMR (DMSO-d6): 6: 1.52-2.24 (m, 5H, 2xCH2 and 0.5xCH2); 2.50-2.88 (m, 3H, ArCH2 and 0.5xCH2); 2.97-3.60 (m, 5H, 2xCH2N and ArCH); 3.67 and 3.69 (2s, 6H, 2xCH30); 3.72 (s, 6H, 2xCH3O); 3,794.11 (m, 2H,
CH2NCO); 6.67-6.85 (m, 4H, Ar); 7.00 (s, 1H, Ar); 7.59 (d, 2H, J = 8.1
Hz, Ar); 8.09 (d, 2H, J = 8.1 Hz, Ar); 10.16 and 11.22 (wide bands, 1H, with with D2O, NH +) ppm.

Example 2
N- [3- (1,2,3,4,4a, 5,6,10b-octahydro-8,9-dimethoxy- benzo- [f] -quinoline-4-yl) -propyl] -N- hydrochloride (3,4-dimethoxyphenyl) -4
nitrobenzamide

 270 mg (0.61 mmol) of 1,2,3,4,4a, 5,6,10b- octahydro-8,9-dimethoxy-N- (3,4-dimethoxyphenyl) -benzo- [f ] quinoline-4-propanamine (D11) and 123 mg (0.64 mmol) of 4-nitrobenzoyl chloride are treated according to the procedure described in example 1 to provide 155 mg (40%) of the desired compound in the form of a yellow solid . P.f. = 155 C.

1H NMR (DMSO-d6): 6: 1.30-2.40 (m, 8H, 4xCH2); 2.65-3.50 (m, 8H, 3xCH2 and 2xCH); 3.55-3.80 (m, 12H, 4xCH30); 3.80-4.10 (m, 2H,
CH2NCO); 6.65-7.10 (m, 5H, Ar); 7.57 (d, 2H, J = 8.5 Hz, Ar); 8.08 (d, 2H, J = 8.5 Hz, Ar); 10.50-10.85 (wide band, 1H, sample with D2O, NH +) ppm.

E - e3
N- [3- (1,2,3,4,4a, 5,10,10a-octahydro-7,8- dimethoxy-benzo- [g] -quinoline-1-yl) -propyl] -N hydrochloride hydrate - (3,4-dimethoxyphenyl)
4-nitrobenzamide

A solution of 189 mg (1.0 mmol) of 4nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise to a solution of 360 mg (0.80 mmol) of 1,2,3,4, 4a, 5,10,10a-
Octahydro-7,8-dimethoxy-N- (3,4-dimethoxyphenyl) -benzo- [gl quinoline-4-propanamine (D13) and 103 mg (1.0 mmol) of triethylamine cooled to 0 C and stirred. The mixture is stirred and allowed to reach room temperature, then stirring is continued for 1 hour. The mixture is washed twice with 10 ml of water, dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a 99/1 mixture of methylene chloride and methanol as eluent, to give 390 mg of a yellow foam which is salified in methanol by addition of an anhydrous HCl solution in diethyl ether to provide 320 mg (62.5%) of the desired compound as a yellow foam.

Pf. = 165-190 C.

1H NMR (DMSO-d6) #: 1.10-2.20 (m, 6H, 3xCH2); 2.50-3.50 (m, 10H, 4xCH2, CHN and CH); 3.50-3.85 (m, 12H, 4xCH30); 3.85-4.10 (m, 2H,
CH2NCO); 6.50-7.10 (m, 5H, Ar); 7.45-7.70 (m, 2H, Ar); 8.00-8.20 (m, 2H, Ar); 10.10-10.55 (wide band, 1H, sample with D20, NH +) ppm.

RU data
Methodology
Guinea pigs (weighing 300 to 350 g) are anesthetized by intravenous injection of sodium pentobarbital (60 mdlog). 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 infused with solution of oxygenated Tyrode, maintained at 37 + 10C.

The modified Tyrode solution (pH 7.35) has the following composition (mM): NaCl 125; KCl 4.0; 0.5 MgCl2; CaCl2 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% CO2.

 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 of 4 to 7 members, saturated or  unsaturated, containing a nitrogen atom, provided that the atom  of nitrogen is not attached to a bridgehead carbon atom and  does not form a bridgehead; A represents an n-C14 alkylene group in which each atom  carbon is optionally substituted with a C16 aryl group; B represents a hydrogen atom or a C1 allyl group; E and F independently represent a bond, a group -CH2- or  -CH2CH2-; D represents a CO, SO2 or NH-CO group; Z represents a bond, a CH2 group, (CH2) 2 or X-CH2-CH2  in which 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, 1H-imidazolyl, allçyl or alkoxy, or else Q represents a substituted or unsubstituted group  substituted selected from the groups fliranyl, pyranyl, thienyl,  thiazolyle, imidazolyle, triazolyle or the equivalent condensed with  a benzo, uranyl, pyranyl, thienyl, thiazolyl group,  imidazolyle, or triazolyle, indolyle, oxoindolyle, indényle,  isoindenyl, indazolyl, indolizinyl, benzofurazanyl or  pyridinyl or cycloalkyl optionally condensed with a group  aryl; R1, R2, R3, R4 and R5 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, R3, R4 and R5 can form with carbon atoms  to which they are attached, a condensed heterocyclic nucleus of five to  six atoms in which one, two or three of these atoms are  oxygen or nitrogen atoms;  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 (it !:

 in which A, B, E, F, J, Z, R1, R2, R3, R4 and R5 are as defined in relation to formula (I), with a compound of formula (III) BL 1 (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 or sO2, L1 represents COX or SO2X respectively, in  which X is a mobile group such as a halogen atom; and (b) for compounds of formula (I) in which D is a group  NH-CO, 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.  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 an acceptable carrier from the pharmaceutical point of view for these.  4. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable salt 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.