FR2729144A1 - New heterocyclic di:amine derivs. - Google Patents

Abstract

Heterocyclic diamine derivs. of formula (I) and their salts and solvates are new. G = a gp. completing a satd. or unsatd. 5- to 7-membered ring; A= (CH2)m; m = 1-3; B = 1-4C n-alkylene in which each C atom is opt. substd. by a 1-6C alkyl gp.; R3 = H, 1-6C alkyl, 2-6C alkenyl or 3-8C cycloalkyl; D = CO, SO2 or NHCO; Q = aryl, aralkyl, aralkenyl or aralkynyl, all opt. ring-substd. by 1-5 of halogen, 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, benzo-furazanyl or pyridyl; or opt. aryl-fused cycloalkyl; R1 and R2 = H, alkyl, OH or alkoxy, or R1 and R2 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 and R2; or opt, substd. heteroaryl.

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 B-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 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 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 ffi 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:
N est un atome d'azote, qui avec G, représente un noyau
hétérocyclique saturé ou insaturé de 5, 6 ou 7 chaînons, condensé
au cycle benzène adjacent;
A représente une liaison ou une partie QCH2)m- dans laquelle m est
un entier de 1, 2 ou 3;
B représente un groupe n-alkylène en C14 dans lequel chaque atome
de carbone est éventuellement substitué par un groupe allyle en C1-6;
R3 représente un atome d'hydrogène, un groupe allyle en C1-6, alcène
en C2 6 ou cycloalkyle en C3;
D représente un groupe CO, SO2 ou NH-CO;;
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 uranyle, pyranyle, thiényle, thiazolyle,
imidazolyle, ou triazolyle, indolyle, oxoindolyle, indényle,
benzofiirazanyle, isoindényle, indazolyle, indolizinyle ou
pyridinyle ou cycloalkyle éventuellement condensé avec un groupe
aryle; R1 et R2 représentent chacun indépendamment un atome
d'hydrogène, un groupe allyle, hydroxy ou alcoxy, ou, s'ils sont
attachés à des atomes de carbone adjacents, les deux R1 et R2
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; et
Ar représente un groupe aryle substitué ou non substitué, dans lequel
les substituants éventuels sont les R1 et R2 définis plus haut, ou Ar
bien représente un groupe hétéroaryle substitué ou non substitué.Consequently, the present invention relates to a compound of formula (I):

or a salt thereof or a solvate thereof, in which:
N is a nitrogen atom, which together with G represents a nucleus
5, 6 or 7-membered saturated or unsaturated heterocyclic, condensed
the adjacent benzene ring;
A represents a bond or a part QCH2) m- in which m is
an integer of 1, 2 or 3;
B represents a C14 n-alkylene group in which each atom
carbon is optionally substituted with a C1-6 allyl group;
R3 represents a hydrogen atom, a C1-6 allyl group, alkene
C2 or C3 cycloalkyl;
D represents a CO, SO2 or NH-CO group;
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, alkoxycarbonyl, aikylamido, aikylsulfonamido, 1H-imidazolyl group,
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 uranyl, pyranyl, thienyl, thiazolyl,
imidazolyle, or triazolyle, indolyle, oxoindolyle, indényle,
benzofiirazanyl, isoindenyl, indazolyl, indolizinyl or
pyridinyl or cycloalkyl optionally condensed with a group
aryl; R1 and R2 each independently represent an atom
hydrogen, an allyl, hydroxy or alkoxy group, or, if they are
attached to adjacent carbon atoms, both R1 and R2
can form with the carbon atoms to which they are attached,
a condensed heterocyclic ring of five or six atoms in
which one, two or three of these atoms are oxygen atoms
or nitrogen; and
Ar represents a substituted or unsubstituted aryl group, in which
the possible substituents are the R1 and R2 defined above, or Ar
bien represents a substituted or unsubstituted heteroaryl group.

 Suitably, the heterocyclic nitrogen atom and the nitrogen atom of the chain are separated by 3 or 4 carbon atoms.

 Suitably, B represents a group -CH2CH2-.

 Suitably, D represents a CO group.

 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 4nitro group.

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

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

 The term "alkenyl" used herein includes straight chain or branched chain alkyl groups having from 2 to 12, preferably from 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, the nitro, amino, cyano, caroxy, alkoxycarbonyl, aikylamido, aikylsulfonamido, 1H-imidazolyl, allyl or alkoxy groups.

 Suitable heteroaryl groups include the indole, benzofuran, benzofurazane and benzothiophene groups, substituted as described herein with respect to the aryl group.

 The term "cycloalkyl" used herein includes carbon-carbon bonds of cycloalkyl group 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) can 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 such as those of formula RY-T in which Ry is a C1-allyl phenyl-C1-alkyl or C57-cycloalkyl group and T is a radical corresponding to an anion of a acid. Suitable examples of R9 include methyl, ethyl and n- and isupropyl, 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, B, G, R1, R2, R3 et Ar sont tels que définis en relation avec la formule (I), avec un composé de formule ("I): B-L 1 (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 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, G, R1, R2, R3 and Ar are as defined in relation to formula (I), with a compound of formula ("I): 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.

 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.

 The compounds of formula (fui) 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 (fui) 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 (m) 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 B, G, R1, R2, R3 et Ar sont tels que définis en relation avec la formule (I) et A1 représente une partie -(CH2)m-i- dans laquelle m est tel que défini en relation avec la formule (I).The compounds of formula (II) can be prepared by reduction of compounds of formula (IV):

in which B, G, R1, R2, R3 and Ar are as defined in relation to the formula (I) and A1 represents a part - (CH2) mi- in which m is as defined in relation to the formula (I ).

 The compounds of formula (II) in which G and N together form a saturated nucleus can preferably be prepared by catalytic reduction of a compound of formula (H) in which G and N together form an unsaturated nucleus as illustrated above.

dans laquelle G, A1, R1 et R2 sont tels que définis dans la formule (IV) et L2 représente un groupe mobile, comme un atome d'halogène, avec un composé de formule (VI):

dans laquelle B, R3 et Ar sont tels que définis en relation avec la formule (I).The compounds of formula (IV) can be prepared by condensation of a compound of formula (V):

in which G, A1, R1 and R2 are as defined in formula (IV) and L2 represents a mobile group, such as a halogen atom, with a compound of formula (VI):

in which B, R3 and Ar are as defined in relation to formula (I).

The compounds of formula (V) can be prepared from the corresponding carboxylic acids according to known procedures, for example, as described in Organic Syntheses
Coll. Flight. I, page 394 and Organic Syntheses Coll. Vol m, page 29.

 The carboxylic acids corresponding to the compounds of formula (V) in which G and N together form an unsaturated nucleus, are known compounds or they are prepared according to procedures analogous to those described for preparing the known compounds, as indicated in Bull. Expensive. Soc.

Japan 1966,39,195 or Synthesis 1973,48.

 The compounds of formula (VI) are known compounds or they can be obtained 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 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 from 10 to 75 mg, i.e. in the range of about 0.002 to 35 mg / lq / day, more generally from 1 to 30 mg / kg / day, for example, from 0 , 15 to 1 mg / kglday.

 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 may contain conventional additives such as suspending agents, for example, sorbitol, a syrup, a methylcellulose, a gelatin, a hydroxyethyl cellulose, a cabboxymethyl 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 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 reactive 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 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 these pharmaceutically acceptable, 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.

Description 1 6,7-Dimethoxy-N- [2- (3,4-dimethoxyphenyl) -ethyl-N-methyl-3

 4.7 g (37.1 mmol) of oxalyl chloride is added dropwise, with stirring and at room temperature, to a suspension of 5 g (18.5 mol) of acid 6.7 -dimethoxy-3-quinoline carboxylic in 60 ml of methylene chloride containing a drop of DMF, with stirring at room temperature. The reaction mixture is stirred for 2 hours, then the solvent is evaporated. The residue is taken up in 50 ml of methylene chloride and cooled to 0 C before being added dropwise to a solution of 2, 98 g (14.8 mmol) of N-3,4 dimethoxybenzeneethanamine and 3.37 g (33.3 mmol) of triethylamine in 50 ml of methylene chloride. Stirring is continued for 16 hours, while the reaction mixture is allowed to reach room temperature. The reaction mixture is then washed with water, with a saturated solution of sodium bicarbonate, again with water, then the organic phase is dried over MgSO4 The solvent is concentrated under vacuum and the residue is purified by chromatography on silica gel eluted with a mixture of methylene chloride / methanol first 99/1, then 97/3, to give 5.8 g (96.7%) of the expected product in the form of a yellow-brown oil. This product still contains some impurities but is used in the next step without further purification.

1H NMR (DMSO-d6): 5 = 2.62-2.99 (m, 2H, CH2); 3.08 (s, 3H,
NCH3); 3.26-3.52 (m, 2H, cH2); 3.73 and 3.92 (2s, 12H, 4xOCH3); 6.4.97 (m, 3H, 3xAr); 7.12-7.52 (m, 3H, 3xAr); 8.35 (s, 1H, Ar) ppm. D - ioei2 1,2,3,4-Tetrahydro-6,7-dimethoxy-N- [2- (3,4-dimethoxyphenyl) -ethyl] -
N-methyl-3-quinoline methanamine

 2.76 g (73.1 mmol) of sodium borohydride is added to a solution of 2 g (4.9 mmol) of 6,7-dimethoxy-N- [2- (3, 4-dimethoxyphenyl) -ethyl ] -N-methyl-3-quinoline carboxamide (D1) in 50 ml of dioxane with stirring.

This solution is cooled to 0 ° C., then 4.38 g (73.1 mmol) of acetic acid are added dropwise. The reaction mixture is then heated for 16 hours at reflux, then poured into 50 ml of ice water. The aqueous phase is extracted with ethyl acetate (4x50ml) and the organic phase is washed with saturated sodium chloride solution, then dried over MgSO4 and finally concentrated in vacuo. The residue is purified by chromatography on silica gel eluted with a 99/1 mixture of methylene chloride / methanol to give 657 mg (29%) of the desired product in the form of a pale yellow oil.

1H NMR (DMSO-d6): # = 1.862.04 (m, 1H, CH); 2.10-2.35 (m, 2H,
CH2); 2.24 (s, 3H, NCH3); 2.45-2.85 (m, 7H, 3.5xCH2); 3.05-3.26 (m, 1H,
O, 5xCH2); 3.59, 3.63, 3.70 and 3.73 (4s, 12H, 4x () CH3); 5.19 (s, 1H, exchange with D2O, NH); 6.11 (s, 1H, Ar); 6.45 (s, 1H, Ar); 6.70 (d, 1H,
J = 8.2 Hz, Ar); 6.75-6.88 (m, 2H, 2xAr) ppm.

D-nioei3 [(5-Methoxy-1H-indol-3-yl) methylene] - [2- (3,4-dimethoxyphenyl) -ethyl] - amine

 A mixture of 0.876 g (5 mmol) of 5-indol-3-carboxaldehyde, 0.905 g (5 mmol) of 3, 4-dimethoxybenzene ethanamine, 40 ml of toluene and a few mg of p-toluenesulfonic acid is heated at reflux for 2 hours while the water formed is trapped by a Dean-Stark apparatus. The reaction mixture is concentrated in vacuo and the residue used in the next step without further purification.

5-Methoxy-N- [2- (3,4-dimethoxyphenyl) -ethyl] -1H-indole-3-methaneamine

 A solution of crude [(5-methoxy- 1H-indol-3-yl) -methylene] - [2- (3,4-dimethoxyphenyl) -ethyl] -amine D3 in 20 ml of ethanol and 20 ml of acid acetic acid is cooled by an ice bath, then added with 0.285 g (7.5 mmol) of sodium borohydride The mixture is stirred overnight at room temperature, then diluted with 100 ml of water and basified with 5N NaOH. mixture is extracted twice with 50 ml of ethyl acetate, then the organic phase is washed three times with 50 ml of water, dried over MgSO4 and concentrated in vacuo to give 1.7 g of the desired product, pure from after thin layer chromatography and used as is in the next step.

Description 5 5-Methoxy-N- [2- (3,4-dimethoxyphenyl) -ethyl] -N-methyl-1H-indol-3 metbaneanaine

 A solution of 1.7 g (5 mmol) of 5-methoxy-N4243,4-dimethoxyphenyl) ethyl] -1H-indole-3-methaneamine D4 in 10 ml of methanol is cooled in an ice bath, then added with 0.175 g of a 40% aqueous formaldehyde solution. Stirring is continued for one hour at 10 ° C., then 0.15 g of sodium borohydride is added at this temperature and stirring is continued for another 30 minutes. The reaction mixture is allowed to reach room temperature, diluted with 50 ml of water and extracted with 50 ml of ethyl acetate. The organic phase is washed three times with 50 ml of water, dried over MgSO 4 and concentrated in vacuo. . The residue is purified by chromatography on silica gel first eluted with pure ethyl acetate, then with a 9/1 mixture of ethyl acetate / methylnol to give 1.4 g (79%) of the residue. desired product as an oil.

1H NMR (DMSO-d6): # = 2.19 (s, 3H, NCH3); 2.57-2.61 (m, 2H,
CH2); 2,692.73 (m, 2H, CH2); 3.64 (s, 2H, CH2); 3.68 (s, 3H, OCH3); 3.69 (s, 6H, 2xOCH3); 6.67-6.83 (m, 4H, Ar); 7.03 (d, 1H, J = 2.3 Hz, Ar); 7.16 (d, 1H, J = 2.3 Hz, Ar); 7.22 (d, 1H, J = 8.7 Hz, Ar); 10.72 (s, 1H, exchange with D20, NH) ppm.

Description 6 6,7-Dimethoxyquinoline 1 oxide

 A solution of 4.8 g (25 mmol) of 6,7-dimethoxyquinoline and 2.3 ml of 30% aqueous hydrogen peroxide in 15 ml of acetic acid is stirred at 700C for 4 hours. An additional 2.3 ml of 30% aqueous hydrogen peroxide is added and stirring is continued at the same temperature for 18 hours. The acetic acid is concentrated under vacuum and 50 ml of water are added. The mixture is made basic with sodium hydroxide, then extracted with methylene chloride. The organic solution is dried over MgSO4 and concentrated in vacuo. The residue is triturated in di- (2-methylethyl) ether to provide 4.4 g (86.3%) of the desired compound as beige crystals. P.f. = 1360C.

1H NMR (CDCl3): 4.01 and 4.08 (2s, 6H, 2xOCH3); 7.08 (s, 1H, Ar); 7.18 (dd, 1H, J1 = 8.3 Hz, J2 = 6.1 Hz, Ar); 7.62 (d, 1H, J = 8.3 Hz); 8.07 (s, 1H, Ar); 8.43 (d, 1H, J = 6.1 Hz, Ar) ppm.

Description 7 6,7-Dimethoxy-2-quinoline-methyl acetate

 A mixture of 4.4 g (21 mmol) of 6,7-dimethoxy quinoline-1-oxide (D6) and 5.9 ml (52 mmol) of methyl 3-oxobutanoate in 20 ml of acetic anhydride is stirred at 40-450C for 16 hours and then poured into ice water. The precipitate is filtered, washed with water and taken up in methylene chloride. The organic solution is dried over MgSO4 and concentrated in vacuo. The residue is taken up in 60 ml of methanol and heated under reflux for 3 hours.

The solvent is concentrated in vacuo to provide 4.05 g (73.8%) of the desired compound.

1H NMR (CDCl3): 5: 3.73 (1s, 3H, CO2CH3); 4.00-4.15 (m, 8H, CH2CO2 and 2xOCH3); 7.04 (s, 1H, Ar); 7.29 (d, 1H, J = 8.0 Hz, Ar); 7.42 (s, 1H, Ar); 7.99 (d, 1H, J = 8.0 Hz) ppm.

Description 8 6,7-Dimethoxy-2-quinoline-ethanol

 2.25 g (8.6 mmol) of 6.7 dimethoxy-2-quinoline-methyl acetate (D7) dissolved in a mixture of 5 ml of THF and 40 ml of diethyl ether is added dropwise dropwise into a mixture of 0.59 g (15.3 mmol) of aluminolithic hydride in 60 ml of ethyl ether stirred and cooled to 0-5 C. The mixture is then heated at reflux for 2 hours and cooled again at 0-5 C. before careful addition of 0.6 ml of water, 0.6 ml of 15% aqueous sodium hydroxide and 1.8 ml of water. The precipitate is separated by filtration, washed with diethyl ether, then in methylene chloride and the organic solutions are mixed and concentrated in vacuo. The residue is triturated in di (2-methylpropyl) ether to give 1.5 g (74.8%) of the desired compound.

1H NMR (CDCl3): 6: 3.15 (t, 2H, J = 5.8 Hz, CH2); 4.0 and 4.03 (25.6H, 2xOCH3); 4.12 (t, 2H, J = 5.8, CH2); 4.30-5.10 (broadband, 1H, scale.

with D20, OH); 7.02 (s, 1H, Ar); 7.15 (d, 1H, J = 8.3 Hz, Ar); 7.35 (d, 1H,
Ar); 7.94 (d, 1H, J = 8.3 Hz) ppm.

Description 9 6,7-Dimethoxy-N- [2- (3,4-dimethoxyphenyl) -ethyl] -N-methyl-2-
quinoline ethanamine

 0.84 g (7.3 mmol) of methanesulfonyl chloride is added dropwise to a mixture of 1.47 g (6.3 mmol) of 6,7-dimethoxy-2-quinolineethanol (D8 ) and 0.96 g (9.5 mmol) of triethylamine in 30 ml of stirred methylene chloride and the mixture is cooled to OOC. The mixture is stirred for an additional hour, then washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with an 8/2 mixture of methylene chloride and ethyl acetate, then a 95/5 mixture of methylene chloride and methanol and then triturated in diethyl ether The compound thus purified is then added to a stirred mixture of 0.59 g (2.9 mmol) of 3,4-dimethoxy-N-methyl-benzeneethanamine and 0.29 g (3.5 mmol) of acetate sodium in 10 ml of a mixture 111 of methanol and water before being heated to reflux for 3 hours. An additional 0.15 g (1.77 mmol) of 3,4-dimethoxy-N-methyl-benzeneethanamine is then added and the corresponding mixture is stirred at reflux for 16 hours. The solvent is concentrated in vacuo and the residue is taken up in methylene chloride, then washed twice with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel with a mixture of 95 / 5/1 methylene chloride, methanol and concentrated aqueous ammonia to provide 0.69 g (27%) of the desired product as a light brown oil.

1H NMR (CDCl3): o: 2.47 (s, 3H, CH3N); 2.6t; 2.85 (m, 4H, 2xCH2N); 2.90-3.25 (m, 4H, 2xCH2); 3.85 (m, 6H, 2xOCH3); 4.00 and 4.03 (2s, 6H, 2xCH30); 6.65-6.85 (m, 3H, Ar); 7.02 (s, 1H, Ar); 7.18 (d, 1H, J = 8.3 Hz,
Ar); 7.38 (s, 1H, Ar); 7.91 (d, 1H, J = 8.3 Hz) ppm.

EXAMPLE 1 [1,2,3,4-Tetrahydro-6,7-dimethoxy-3 - [[[2- (3,4-dimethoxyphenyl) -ethyl] -methylamino] methyl] -1-quinolinyl] hydrochloride hemihydrate hydrochloride (4-nitrophenyl) -methanone

 A solution of 0.70 g (3.8 mmol) of 4nitrobenzoyl chloride in 40 ml of methylene chloride is added dropwise, with stirring, to a solution cooled to 0 C, of 1.2 g (3 mmol) 1,2,3,4-tetrahydro-6,7-dimethoy-N- [2- (3,4-dimethoUphenylSethyl] -N-methyl-3suinoline methanamine (D2) and 0.385 g (3.8 mmol) of triethylamine in 40 ml of methylene chloride. Stirring is continued for 16 hours while the mixture is allowed to reach room temperature. The reaction mixture is washed twice with 20 ml of water, then the organic phase is dried over MgSO4 and concentrated in vacuo The residue is purified by chromatography on silica gel successively by elution with a 99/1 mixture of methylene chloride / methanol, then with a 99 / 0.5 / 0.5 mixture of methylene chloride, methanol and triethylamine and finally with the same mixture in the proportions 99.6 / 0.2 / 0.2. The base obtained is salified in ns methanol by adding an anhydrous dXCl solution in diethyl ether to give 298 mg (17%) of the desired product in the form of an orange foam.

P. = 1200C
1H NMR (DMSO-d6): 5 = 2,582.7 &, 2H, CH2); 2.87 (s, 3H, NCH3), 2.93-3.43 (m, 7H, 3xCH2, CH); 3.62-3.88 and 4.08-4.39 (2m, 2H, CH2); 3.73 (s, 12H, 4xOCH3); 6.72-6.98 (m, 5H, 5xAr); 7.64 (d, 2H, J = 8.4Hz, 2xAr); 8.22 (d, 2H, J = 8.4Hz, 2xAr), 10.12 (s broad, 1H, exchange with D20,
NH +) ppm.

Example 2 [5-Methoxy-3 - [[[2- (3,4-dimethoxyphenyl) -ethyl] -methylamino] methyl] 1H-indolyl] - (4-nitrophenyl) -methanone.

0.189 g (7.8 mmol) of NaH (55% dispersion in mineral oil) is added at 100 ° C. to a solution of 1.4 g (4 mmol) of 5-methoxy-N- [2- ( 3,4-dimethoxyphenyl) -ethyl] -N-methyl-1H-indol-3-methaneamine (D5) in 30 ml of DMF, then stirring is continued for one hour. A solution of 0.75 g (4 mmol) of p-nitrobenzoyl chloride in 5 ml of DMF is then added dropwise and stirring is continued for 2 hours.

The mixture is concentrated in vacuo and the residue is redissolved in 75 ml of ethyl acetate. The organic solution is washed three times with 50 ml of water, dried over MgSO4, then concentrated in vacuo. The residue is purified by chromatography on silica gel successively eluted first with pure ethyl acetate, then with a 4/1 mixture of methylene chloride / ethyl acetate to give 0.150 g (7.5%) of the desired product.

1H NMR (DMSO-d6): 5 = 2.19 (s, 3H, NCH3); 2.61-2.70 (m, 4H, 2xCH2); 3.60 (s, 2H, CH2); 3.66 (s, 3H, OCH3); 3.69 (s, 3H, OCH3); 3.73 (s, 3H, OCH3); 6.66-6.81 (m, 3H, 3xAr); 7.00 (dd, 1H, J = 8.9Hz, J = 2.3Hz,
Ar); 7.16 (s, 1H, Ar); 7.19 (d, 1H, J = 2.3 Hz, Ar); 8.00 (d, 2H, J = 8.5Hz, 2xAr); 8.20 (d, 1H, J = 8.9 Hz, Ar); 8.40 (d, 2H, J = 8.5Hz, 2xAr) ppx
Ez-fl-3 hydrochloride [1,2,3,4-tetrahydro-6,7-dimethoxy-2- [2 - [[2- (3,4-
dimethoxyphenyl) -ethyl] -methylamino] -ethyl] -1-quinolinyl] - (4nitrophenyl) -methanone.

 0.64 g (1.56 mmol) of 6,7-dimethoxy-N- [2- (3, 4-dimethoxyphenyl) -ethyl] -N-methyl-2-quinoiine-ethana (D9) in 40 ml of ethanol and 0.3 ml of chloroform is hydrogenated on 150 mg of PtO2 at 30 C under a pressure of 30 bars. The catalyst is filtered off and the solvent is concentrated in vacuo. The residue is taken up in water and the solution is basified with aqueous NaOH, then extracted with methylene chloride, dried over MgSO4, then concentrated in vacuo. The residue is purified by chromatography on silica gel eluted with a mixture 95 / 5 of methylene chloride and methanol, then taken up in 10 ml of methylene chloride and 56 mg (0.55 mmol) of triethylamine, stirred and cooled to 0-50C before addition of 102 mg (0.55 mmol) of 4-nitrobenzoyl chloride. The mixture is stirred for 2 hours at 5-10 ° C., 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 an 8/2 / 0.7 mixture of methylene chloride, ethyl acetate and methanol. It is salified in methanol by addition of a solution of anhydrous HCl in diethyl ether, then triturated four times in diethyl ether to provide 139 mg (15% of the desired compound in the form of yellow crystals. Pf = 120 -130 C.

1H NMR (DMSO d6): # = 1.50-2.50 (m, 4H, 2xCH2); 2.65-2.85 (m, 5H,
CH2 and NCH3); 2.85-3.05 (m, 2H, CH2); 3.05-3.40 (m, 7H, 2xCH2 and
OCH3); 3.71, 3.72 and 3.74 (3s, 9H, 3x0CH3); 4.6a.4.95 (m, 1H, CHNCO); 6.10-6.25 (s, 1H, Ar); 6.65-7.00 (m, 4H, Ar); 7.40-7.65 (m, 2H, Ar); 8,108.25 (m, 2H, Ar); 10.15-10.45 (broadband, 1H, edL with D20, NH +) ppm.

Back È -
Guinea pigs (weighing 300 to 350 g) are anesthetized by intravenous injection of sodium pentobarbital (60 mg / log). 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 + 10C.

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: N is a nitrogen atom, which together with G represents a nucleus  5, 6 or 7-membered saturated or unsaturated heterocyclic, condensed  the adjacent benzene ring; A represents a bond or a part - (CH2) m- in which m is  an integer of 1, 2 or 3; B represents an n-C 1 alkylene group in which each atom  carbon is optionally substituted with a C1-6 alkyl group; R3 represents a hydrogen atom, a C1-6 allyl group, alkene  C26 or C3 cycloalkyl; D represents a group CO, SO2 or NH-CO; 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-imidazolyle,  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, indényle,  benzofurazanyl, isoindenyl, indazolyl, indolizinyl or  pyridinyl or cycloalkyl optionally condensed with a group  aryle ;; R1 and R2 each independently represent an atom  hydrogen, an allyl, hydroxy or alkoxy group, or, if they are  attached to adjacent carbon atoms, both R1 and R2  can form with the carbon atoms to which they are attached,  a condensed heterocyclic ring of five to six atoms in which  one, two or three of these atoms are oxygen atoms or  nitrogen; and Ar represents a substituted or unsubstituted aryl group, in which  the possible substituents are the R1 and R2 defined above, or  although Ar represents a substituted or unsubstituted heteroaryl group  substituted.  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, B, G, R1, R2, R3 and Ar are as defined in relation to formula (I), with a compound of formula (III):  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 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 salt thereof and a carrier acceptable from the pharmaceutical point of view for these.  4. A compound of formula (I) as claimed in 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 salt thereof that is pharmaceutically acceptable and / or a solvate thereof pharmaceutically acceptable, useful in the treatment and / or prophylaxis of arrhythmia.