FR2729140A1 - New cyclo-alkylene-di:amine derivs - Google Patents

Abstract

Cycloalkylene-diamine derivs. of formula (I) and their salts and solvates are new. T = a 1,2-, 1,3- or 1,4-linked, opt. unsatd. 3-7C carbocyclic gp.; A, A1 = a bond, CH2 or CH2CH2; B = 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 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, oxo-indolyl, indenyl, iso-indenyl, indazolyl, indolizinyl, benzofurazanyl 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. 5-6 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; or B+B4 = a 3- to 7-membered ring.

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.

Anti-arythinic 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 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 anti-arrhythmic agents of class m block the potassium cardiac 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 III compounds currently under development.

 It has been discovered that certain new amine derivatives 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 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 ou à un solvate de ceux-ci, dans laquelle:
T représente un cycle carbocyclique de 3 à 7 chaînons, saturé ou
insaturé, substitué par A et A1 qui sont en positions 1-2, 1-3 ou 1,4
l'un par rapport à l'autre;
A et Ai représentent chacun indépendamment une liaison, un groupe
-CH2- ou -CH2CH2-;
B représente un groupe n-alkylène en C1 dans lequel chaque atome
de carbone est éventuellement substitué par un groupe alkyle en
C1-6;
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, aralayle, 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, gamme, cyano, carboxy,
alcoxycarbonyle, alkylamido, alkylsulfonamido, 1H-imidazolyle,
allyle ou alcoxy, ou bien Q représente un groupe substitué ou non
substitué choisi parmi les groupes uranyle, pyranyle, thiényle,
thiazolyle, imidazolyle, triazolyle ou les équivalents condensés avec
un groupe benzo de furanyle, pyranyle, thiényle, thiazolyle,
imidazolyle, ou triazolyle, indolyle, oxoindolyle, indényle,
isoindényle, indazolyle, indolizinyle, benzofurazanyle ou
pyridinyle, ou cycloalkyle éventuellement condensé avec un groupe
aryle;
R1, R2 et R3 représentent chacun indépendamment un atome
d'hydrogène, un groupe allyle en C1-6, hydroxy ou alcoxy en C14,
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 cinq ou six atomes dans lequel un, deux ou trois de ces atomes
sont des atomes d'oxygène ou d'azote;
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 est un atome d'hydrogène, un groupe allyle en C1-6, alcène en
C2, ou cycloalkyle en CSg, ou
B et R4 représentent ensemble un noyau carbocyclique de 3 à 7
chaînons.Consequently, the present invention relates to a compound of formula (I):

or a salt thereof or a solvate thereof, in which:
T represents a 3 to 7-membered carbocyclic ring, saturated or
unsaturated, substituted by A and A1 which are in positions 1-2, 1-3 or 1.4
relative to each other;
A and Ai each independently represent a bond, a group
-CH2- or -CH2CH2-;
B represents a C1-alkylene group in which each atom
of carbon is optionally substituted with an alkyl group
C1-6;
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, aralayl, 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 group, range, cyano, carboxy,
alkoxycarbonyl, alkylamido, alkylsulfonamido, 1H-imidazolyle,
allyl or alkoxy, or Q represents a substituted or unsubstituted group
substituted chosen from the uranyl, pyranyl, thienyl groups,
thiazolyle, imidazolyle, triazolyle or the equivalent condensed with
a benzo group of furanyl, pyranyl, thienyl, thiazolyl,
imidazolyle, or triazolyle, indolyle, oxoindolyle, indényle,
isoindenyl, indazolyl, indolizinyl, benzofurazanyl or
pyridinyl, or cycloalkyl optionally condensed with a group
aryl;
R1, R2 and R3 each independently represent an atom
hydrogen, a C1-6 allyl, hydroxy or C14 alkoxy group,
or, if they are attached to adjacent carbon atoms, two
any of R1, R2 and R3 can form with the atoms of
carbon to which they are attached, a condensed heterocyclic nucleus
of five or six atoms in which one, two or three of these atoms
are oxygen or nitrogen atoms;
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 is a hydrogen atom, a C1-6 allyl group, an alkene
C2, or cycloalkyl in CSg, or
B and R4 together represent a carbocyclic ring from 3 to 7
links.

 Suitably, B represents a group (CH2) 2.

 Suitably, D represents a CO group.

 Suitably, Z represents a bond.

 Suitably, A represents a bond or a group -CH2-.

 Conveniently, A1 represents a group -CH2-.

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

 An example of a substituent for Q is a nitro group, such as a Snitro group.

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

 Suitably, R4 represents an EH3 group.

 Suitably, T represents a cyclopropyl, cyclopentyl or cyclohexyl group.

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

 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 a maximum of five, preferably three groups, selected from a halogen atom , nitre, amino, cyano, carboxy, alkoxycarbonyl, allcylamido, alkylsulfonamido, 1H-imidazolyl, allyl or alkoxy groups.

 Suitable heteroaryl groups include the indole, benzofuran, benzofiirazane and benzothiophene groups.

 Substituents suitable for any heteroaryl group include those described herein for the aryl group.

 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, alpha-keto-glutaric, glycerophosphoric 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 formula D-T1 in which RY is a C1-6 allyl group, C14 phenyl-alkyl or C7 cycloalkyfe and T1 is a radical corresponding 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, T1 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 the compounds of formula (I) which are not acceptable from the pharmaceutical point of view can be useful as intermediates in the preparation of the pharmaceutically acceptable salts or solvates of compounds of formula (I) or the compounds of formula (I) themselves, and as such, form an aspect of the present invention.

dans laquelle A, A1, B, R1, R2, R3, R4, T, Z et Ar sont tels que définis en relation avec la formule (I), avec un composé de formule (m) :
Q-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 SO2, L1 représente COX ou sO2x 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) et/ou d1un 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, A1, B, R1, R2, R3, R4, T, Z and Ar are as defined in relation to formula (I), with a compound of formula (m):
Q-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 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.

 The reaction conditions used to carry out the reaction between the compound of formula (II) and the compound of formula (E) 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 or elevated temperature, conveniently at 0 C or at asbestos 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 (III) 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 (E) in which L1 represents an SO2-X group can be prepared according to procedures described in Organic Syntheses Co.

Flight. VIII, page 104 and compounds of formula (III) in which L1 represents a group -N = C = O can be prepared according to procedures described in Organic Syntheses Coll. Flight. m, page 846.

dans laquelle B, R1, R2, R3, R4, T, Z et Ar sont tels que définis en relation avec la formule (I).The compounds of formula (II) in which A is a CH2 group can be prepared by reduction of a compound of formula (IV):

in which B, R1, R2, R3, R4, T, Z and Ar are as defined in relation to formula (I).

 The reduction of the compounds of formula (IV) can be carried out according to conventional procedures, for example, with reducing agents of complex metal hydride type, such as aluminlithic hydride, for example, as described in EP0.233.762.

dans laquelle B, R4, T et Ar sont tels que définis en relation avec la formule (I) et L2 est un groupe mobile, qui est un atome d'halogène, avec un composé de formule (VI):

dans laquelle R1, R2, R3 et Z sont tels que définis en relation avec la formule (I); soit (ii) par condensation d'un composé de formule (VII):

dans laquelle R1, R2, R3, Z et T sont tels que définis en relation avec la formule (I) et L3 est un groupe mobile, qui est un atome d'halogène, avec un composé de formule (vu) :

dans laquelle B, R4 et Ar sont tels que définis en relation avec la formule (I).The compounds of formula (IV) can be prepared either: (i) by condensation of the compounds of formula (V):

in which B, R4, T and Ar are as defined in relation to formula (I) and L2 is a mobile group, which is a halogen atom, with a compound of formula (VI):

wherein R1, R2, R3 and Z are as defined in relation to formula (I); either (ii) by condensation of a compound of formula (VII):

in which R1, R2, R3, Z and T are as defined in relation to formula (I) and L3 is a mobile group, which is a halogen atom, with a compound of formula (seen):

in which B, R4 and Ar are as defined in relation to formula (I).

dans laquelle T est tel que défini en relation avec la formule (I), avec soit une amine de formule (Vm) telle que définie plus haut pour préparer des composés de formule (V), soit avec une amine de formule (VI) telle que définie plus haut pour préparer des composés de formule (VII); et (b) ensuite, par conversion de la fonction acide ainsi formée en un halogénure d'acide, par exemple, un chlorure.Compounds (V) and (VII) can be prepared in two stages: (a) by condensation of an anhydride of formula (IX):

in which T is as defined in relation to formula (I), with either an amine of formula (Vm) as defined above for preparing compounds of formula (V), or with an amine of formula (VI) such as defined above for preparing compounds of formula (VII); and (b) then, by conversion of the acid function thus formed into an acid halide, for example, a chloride.

 The two stages used in the preparation of the compounds of formulas (V) and (VII) are carried out under conventional conditions, for example, those which are described in the Journal of Medicinal Chernistry, 1993, 36, 699.

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

dans laquelle T, A1, B, R4 et Ar sont tels que définis en relation avec la formule (I), avec un composé représenté par la formule (VI) définie plus haut, puis réduction, de préférence in situ de l'imide intermédiaire, selon des procédures classiques, par exemple, celles qui sont décrites dans le Journal of Medicinal Chemistry, 1977,20, 1111. The compounds of formula (II) in which A is a bond, can be prepared by condensation of a ketone of formula (X):

in which T, A1, B, R4 and Ar are as defined in relation to formula (I), with a compound represented by formula (VI) defined above, then reduction, preferably in situ, of the intermediate imide , according to conventional procedures, for example, those described in the Journal of Medicinal Chemistry, 1977, 20, 1111.

The compounds of formula (X) can be prepared by condensation of a compound of formula (XI):
OT (xI) in which T is as defined in relation to formula (I), with a compound of formula (VIT) as defined above, under conventional conditions, such as the conditions of a Mannich condensation reaction , for example, as described in Organic Reactions 1, 303.

 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 methods of formation and elimination of these protecting groups are the conventional methods 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 mammal. 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 10 to 75 mg, i.e. in the range of about 0.002 to 35 mg / day, more generally 1 to 30 mg / kg / day, for example, 0.15 to 1 mgssgfday.

 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, polymnylpyrrolidone 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 p-hydroxybenzoate or sorbic acid, and if desired, conventional coloring agents or 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 be able to also 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, Denier) 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" encompasses 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 administering 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 of those 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 a pharmaceutical point of view. from a pharmaceutical point of view, for the manufacture of a medicament for the treatment of arrhythmia, in particular 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
Cis-2 acid - [[[2- (3,4-Dimethoxyphenyl) ethyl] methylamino] carbonyl] cyclohexanecarboxylic

A mixture of 6.16 g (40 mmol) of cis-1,2-cyclohexanedicarboxylic anhydride and 7.85 g (40 mmol) of N-methyl-2- (3,4-dimethoxyphenyl) -ethylamine is heated for one hour at 60 C. When the mixture has returned to room temperature it is poured into 200 ml of water and then extracted twice with 100 ml of ethyl acetate. The organic phase is washed with water, dried over MgSO4 and then the solvent is concentrated under vacuum.

The residue is triturated in ethyl ether and the crystals thus obtained are filtered, dried and useful without further purification in the next step. RdL 8.44g (92.5%).

Description 2
Trans-2 - [[[2- (3,4-Dimethoxyphenyl) ethyl] methylamino] carbonyl] cyclohexane carboxylic acid

The procedure dc in description 1 is repeated starting from 5 g (32 mmol) of trans-1,2-cyclohexanedicarboxylic anhydride and makes it possible to obtain 7.7 g (68%) of the desired compound.

Description 3
Cis-2 chloride - [[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] carbonyl] cyclohexanecarbonyl.

A solution of 1.3 g (10 mmoles) of oxalyl chloride in 10 ml of methylene chloride is added dropwise to a solution of 3.49 g (10 mmoles) of acid case 2 - [[[2- (3,4 -dimethoxyphenyl) ethyl] methylamino] carbonyl] -cyclohexanecarboxylic (D1) in 20ml of methylene chloride plus a drop of DMF. The mixture is stirred until the end of gas evolution. The solvent is concentrated in vacuo and the product is used without purification in the next step.

Description 4
Trans-2 - [[[2- (3,4-Dimethoxyphenyl) ethyl] methylamino] carbonyl] cyclohexanecarbonyl chloride.

The procedure of description 3 is repeated starting from 5 g (14 mmoles) of trans-2 acid - [[[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] carbonyl] cyclohexanecarboxylic acid (D2) and makes it possible to obtain the desired acid chloride, which will be used crude in the next step.

Description S cis-N- (3,4-Dimethoxyphenyl) -N '- [[2- (3-, 4-dimethoxyphenyl) ethyl] methylamino] 1,2-cyclohexanedicarboxamide.

 The crude chloride of cis-2 acid - [[[2- (3,4dimethoxyphenyl) ethyl] methylamino] carbonyl] -cyclohexanecarboxylic acid (D3) is dissolved in 10 ml of methylene chloride, and is added at room temperature to a mixture 1.53 g (10 mmoles) of 3,4-dimethoxybenzeneamine and 1 g (10 mmoles) of triethylamine in 50 ml of methylene chloride. The mixture is stirred for two hours then the solvent is concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed successively with: 100 ml of water, 100 ml of 1N aqueous HCl, 10 ml of 1N aqueous sodium hydroxide and finally with water until neutral. The organic phase is dried over MgSO4 and concentrated in vacuo to give 2.5g (56%) of the desired product in the form of a semi-crystallized paste.

The proton NMR spectrum is compatible with the announced structure and shows the presence of two forms.

Description 6 trans-N- (3,4-Dimethoxyphenyl) -N '- [[2- (3,4dimethoxyphenyl) ethyl] methylamino] -1,2- cyclohexanedicarboxamide.

 The procedure dc in description 5 is repeated starting from the chloride tut of trans-2 - [[[2- (3,4-dimethoxyphenyl) ethyl] methylamino] carbonyl] cyclohexanecarboxylic acid (D4) and allows to obtain 5g of the desired product.

Description 7 cis-N- (3,4-Dimethoxyphenyl) -N '- [[2- (3,4-dimethoxyphenyl) ethyl] methylamino] 1,2-cyclohexanedimethaneamine.

0.75g (200mmol) of LiAlH4 is carefully added to a solution of 2.5g (5.16mmol) of cis-N- (3,4-dimethoxyphenyl) -N '- [[2- (3,4dimethoxyphenyl) ethyl ] methylamino] -1,2-cyclohexane dicarboxamide (D5) in 50ml of ethyl ether and 25ml of THF, then the reaction mixture is brought to reflux for 3 hours. After returning to ambient temperature, the mixture is treated successively with: 1 ml of water, 1 ml of 15% aqueous sodium hydroxide then 3 ml of water. The solid is removed by filtration on a layer of Celite. The solution is dried over MgSO4 and then concentrated under vacuum. The residue is purified by chromatography on silica gel eluted with a 111 methylene chloride / methyl acetate mixture to give lg (42.5%) of the desired product
Description 8 trans-N- (3,4-Dimethoxyphenyl) -N '- [[2- (3,4dimethoxyphenyl) ethyl] methylamino] -1,2-cyclothexanedimethaneamine.

The procedure of description 7 is repeated, starting from 2 g of trans-N- (3,4dimethoxyphenyl) -N '- [[2- (3,4-dimethoxyphenyl) ethyl] methylamino] -1,2- cyclohexane dicarboxamide ( D6) and makes it possible to obtain 0.5 g of the desired product.

D-, tim9

 A mixture of 11.7 g (50 mmol) of 3,4dimethoxy-N-methyl-benzeneethanamine hydrochloride, 10.28 ml (99.2 mmol) of cyclohexanone and 1.5 g of paraformaldehyde in 20 ml of acid acetic acid is stirred and heated at 80 ° C. for 2.5 hours. The solvent is concentrated in vacuo and the residue is triturated successively with diethyl ether, then in 20 ml of 2-propanone, providing 11.69 g (68.4%) of the desired compound. Pf. = 132 C.

1H NMR (CDCl3) #: 1.25-2.00 (m, 4H, 2xCH2); 2.053.00 (m, 8H,
CH2, CH2CO, CH3NH and CHCO); 3.00-3.75 (m, 6H, 2xCH2N and CH2); 3.84 and 3.86 (2s, 6H, 2xOCH3); 6.70-6.90 (m, 3H, Ar); 12.10-12.30 (wide band, 1H sample with D2O, NH +) ppm.

Description 10 3,4-Dimethoxy-N - [[2 - [(3,4-dimethoxyphenyl) -amino] -cyclohexyl] methyl] -N-methyl] -benzeneethanamine

A mixture of 5.12 g (33 mmol) of 3,4-dimethoxy benzeneamine, of 8.5 g (20 mmol) of 2 - [[[[2- (3,4-dimethoxyphenyl) - ethyl] -methylamino] - methyl] -cyclohexanone (D9) and 5.8 ml (29 mmol) of 5N HCl in methanol, in 130 ml of methanol is stirred at room temperature for 5 minutes, an amount of 1.4 g (21 mmol) sodium cyanoborohydride is then added and the mixture is again stirred at room temperature for 2.5 days. The solvent is concentrated in vacuo and the residue is taken up in water, made basic by addition of sodium hydroxide and extracted with methylene chloride. The organic solution is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified twice by chromatography on silica gel with a mixture first of 95/5, then 90/10 of methylene chloride and methanol, then a 95/5 mixture of ethyl acetate and triethylamine to provide 626 mg (7.0%) of the desired compound as a yellow oil.

1H NMR (DMSO-d6): #: 0.85-2.00 (m, 8H, 4xCH2); 2.05-2.25 (m, 4H,
CH2 and CH3N); 2.40-2.75 (m, 6H, 3xCH2); 2.75-3.00 (m, 1H, CHNH); 3.60, 3.66, 3.69 and 3.71 (4s, 12H, 4xCH30); 5.65-5.90 (broad band, 1H, sample with D2O, NH); 5.98 (dd, 1H, J1 = 8.55 Hz, J2 = 2.3 Hz, Ar); 6.70 (d, 1H, J = 2.3 Hz, Ar); 6.60-6.85 (m, 4H, Ar) ppm.

Example 1
Cis-N- (3,4-dimethoxyphenyl) -N- [2 - [[[2- (3,4

 A solution of 0.41 g (2.2 mmol) of p nitrobenzoyl chloride in 5 ml of methylene chloride is added dropwise to a stirred and ice-cold solution of 1 g (2.2 mmol) of cis- N (3,4-dimethoxyphenyl) -N '- [[2- (3,4-dimethoxyphenyl) -ethyl] methylamino] -1,2- cyclohexanedimethaneamine (D7) and 0.22 g (2.2 mmol) of triethylamine in 20 ml of methylene chloride.

At the end of the addition, stirring is continued for 1 hour. The
solvent is concentrated in vacuo and the residue obtained is dissolved in
100 ml of ethyl acetate, then washed successively with 100 ml
of water, 100 ml of IN aqueous sodium hydroxide and 100 ml of water. The organic phase is dried over MgSO4, then concentrated in vacuo. The residue is purified by chromatography on silica gel and eluted with
a 95/5 mixture of ethyl acetate / methanol to give 0.75 g (59%) of the desired product in the form of an amorphous solid.

 This product is dissolved in 30 ml of ethyl ether and a solution of anhydrous HCl in ether is added to it. The mixture is then concentrated in vacuo to provide 0.75 g of a yellow solid.

M.p. = 115-120 C.

1H NMR (DMSO-d6): # = 1.1-1.9 (broad m, 10H, 4xCH2, 2xCH); 2.8 (s, 3H, CH3); 2.8-3.3 (broad m, 6H, 3xCH2); 3.6-3.8 (m, 1211, 4xOCH3); 3.6-4 (broad m, 2H, CH2); 6.67-6.94 (m, 6H, Ar); 7.49-7.56 (m, 2H, Ar), 8.0-8.10 (m, 2H, Ar); 9.9 (s, 1H, exchange with D2O, NH +) ppm.

Example 2
Trans-N- (3,4-Dimethoxyphenyl) -N- [2 - [[[2- (3,4
dimethoxyphenyl) -ethyl] -methylamino] methyl] -cyclohexylmethyl]

 The procedure of Example 1 is repeated with 0.5 g (1.1 mmol) of trans-N- (3,4-dimethoxyphenyl) -N '- [[2- (3,4-dimethoxyphenyl) -ethyl ] -methylamino] -1,2-cyclohexane-dimethaneamine (D8) and makes it possible to obtain 0.225 g (32%) of the desired product in the form of an amorphous yellow solid. P.f. about 115 C.

1H NMR (DMSO-d6): # = 1.1-1.9 (broad m, 10H, 4xCH2, 2xCH); 2.8 (s, 3H, CH3); 2.8-3.3 (broad m, 6H, 3xCH2); 3.6-3.8 (m, 12H, 4xOCH3); 3.6-4 (broad m, 2H, CH2); 6.71-6.94 (m, 6H, Ar); 7.49-7.56 (m, 2H, Ar); 8.0-8.08 (m, 2H, Ar); 9.86 (s, 1H, exchange D2O, NH +) ppm.

Example 3
N-3,4-dimethoxyphenyl) -N- [2 - [[[2- (3,4dimethoxyphenyl) -ethyl] -methylamino] -methyl] -cyclohexyl] hydrochloride hemihydrate

 A mixture of 400 mg (0.90 mmol) of 3,4-dimethoxy-N [[2 - [(3,4-dimethoxyphenyl) -amino] -cyclohexyl] -methyl] -N-methyl] benzeneethanarnine (D10), 180 mg (0.95 mmol) of nitrobenzoyl chloride and 0.14 ml (0.99 mmol) of triethylamine in 15 ml of methylene chloride, is stirred at room temperature for 16 hours, then washed with water, dried over MgSO4 and concentrated in vacuo.

The residue is purified twice by chromatography on silica gel with a 95/5 mixture of methylene chloride and methanol, then with ethyl acetate to provide 320 mg of a yellow solid. It is then salified twice by adding a solution of anhydrous HCl in diethyl ether to give 256 mg (45%) of the desired compound in the form of yellow crystals. P.f. = 138 C.

1H NMR (DMSO-d6): 6: 1.00-2.40 (m, 8H, 4xCH2); 2.75-3.15 (m, 5H,
CH2N and CH3N); 3.20-3.55 (m, 5H, CH and 2xCH2); 3,553.90 (m, 12H, 4xOCH3); 4.00-4.60 (broadband, 1H, CHNCO); 6.65-7.00 (m, 6H, Ar); 7.55-7.70 (m, 2H, Ar); 7.95-8.00 (m, 2H, Ar); 9.45-9.80 (wide band, 1H, sample with D2O, NH +) ppm.

Pharmacological data
Methodology
Guinea pigs (weighing 300 to 350 g) are anesthetized by intravenous injection of sodium pentobarbital (60 mdlkg). 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's 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 the eqlibre with a gas mixture of 95% 02/546 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).

The signals are monitored on a storage oscilloscope (GOURD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for later 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: T represents a 3 to 7-membered carbocyclic ring, saturated or  unsaturated, substituted by A and A1 which are in positions 1-2, 1-3 or 1.4  relative to each other; A and A1 each independently represent a bond or a  -CH2- or -CH2CH2- group; B represents a C1-4 n-alkylene group in which each atom  of carbon is optionally substituted with an alkyl group  C1-6; D represents a group CO, SO2 or Z represents a bond, a CH2 (CH2) 2 or X-CH2-CH2 group  in which 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, nitro, amino, cyano, carboxy, alkoxycarbonyl, aikylamido, aikylsulfonamido, 1H-imidazolyl,  aryl or alkoxy, or 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, furanyl, pyranyl, thienyl, thiazolyl group,  imidazolyle, or triazolyle, indolyle, oxoindolyle, indényle,  isoindenyl, indazolyl, indolizinyl, benzofiirazanyl or  pyridinyl, or cycloallryl possibly condensed with a group  aryl; R1, R2 and R3 each independently represent an atom  hydrogen, a C1-6 allyl, hydroxy or C1-6 alkoxy group,  or, if they are attached to adjacent carbon atoms, two  any of R1, R2 and R3 can form with the atoms of  carbon to which they are attached, a condensed heterocyclic nucleus  of five or six atoms in which one, two or three of these atoms  are oxygen or nitrogen atoms; 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 is a hydrogen atom, an allyl group at C16, alkene at  C2-6, or C cycloaalyl, or B and R4 together represent a carbocyclic ring from 3 to 7  links.  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 compound of formula (II):

 in which A, A1, B, Ri, R2, R3, R4, T, Z and Ar are as defined in relation to formula (I), with a compound of formula (III):  Q-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 SO2, 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 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.