MXPA97003112A - Nitro-benzamides useful as agentesantiarritmi - Google Patents

Abstract

The present invention relates to a compound of formula (I), or a salt thereof or a solvate thereof, wherein: Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if adjacent carbon atoms are joined, any two substituents together with the carbon atoms to which they are attached can form a fused heterocyclic ring of five to six atoms in which one, two or three of said atoms are oxygen or nitrogen; n-C 1-4 alkylene group in which each carbon is optionally substituted by one or two C 1-6 alkyl groups, R 1 represents hydrogen, alkyl, alkenyl or cycloalkyl, one or two of the group of R 2, R 3 and R 4 represents nitro and the remaining members of the group of R2 R3 and R4 represent hydrogen, X represents a portion -CO-NH-: and Z represents a n-alkylene group of C2-4 wherein each carbon is optionally substituted by one or two groups C 1-6 alkyl, a process for preparing such compounds, pharmaceutical compositions consisting of such compounds and the use of such compounds in

Description

NITRO-BENZQflTDflS USEFUL AS QNTIFlRRITNITIONAL AGENTS DESCRIPTIVE MEMORY The invention relates to certain novel compounds, to pharmaceutical compositions containing said compounds, to a process for the preparation of such compounds and to the use of such compounds as active therapeutic agents. Antiarrhythmic agents are classified according to their electrophysiological effects on the cardiac cell (Vaugham-Uilliams, 1970, 19B9): class I agents block the rapid sodium current, class II agents are beta-adrenergic blockers, class agents III block potassium currents, clade IV agents block the calcium current and class V agents are inhibitors of the specific sinoatrial node. A majority of ventricular and atrial arrhythmias are related to the reentrant circuit. The prolongation of iocardial contumacy within or surrounding such a reentrant circuit is a potential mechanism for the management of cardiac arrhythmias. Because class III antiarrhythmic agents block cardiac potassium currents, they prolong the process of repolarization and increase contumacy. Consequently, class III agents represent the most specific class to treat reentrant arrhythmias. However, due to its mechanism of action, that is, a concentration-dependent increase in the potential duration of cardiac action, higher doses of class III antiarrhythmic agents may trigger arrhythmias. Such arrhythmias, called Torsade de Pointe, represent the main adverse effect of all pure class III compounds currently under development. European patent application publication number 0 245 997, discloses certain indoxysulphoanilides which are noted to have class III pure antiarrhythmic properties. It has now been discovered that certain novel derivatives of substituted 4-nitrobenzamide induce a self-limiting increase in the potential duration of cardiac action, related to a double blockade of the cardiac potassium and calcium channels. Accordingly, they are considered to be useful antiarrhythmic agents with an improved pharmacological profile over pure class III antiarrhythmic agents, and in particular they are considered to exhibit a low proarritrnic potential and easily re-establish the contractile function of the ischemic myocardium. They are considered particularly useful for the treatment of atrial or ventricular cardiac arrhythmias. Accordingly, the invention relates to a compound of formula (I): or a salt thereof or a solvate thereof, wherein Rr represents substituted or insubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms, any two substituents together with the carbon atoms to which they are attached can form a fused heterocyclic ring of five to six atoms in which one, two or three of said atoms are oxygen or nitrogen; R represents an n-alkylene group of C _ in which each carbon is optionally substituted by one or two alkyl groups of Ca .- *; R represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of Ra, Ra and R * represents nitro and the remaining members of the group of Ra, Ra and R * represent hydrogen; X represents a -CO-NH- moiety; and Z represents an n-alkylene group of Ca_ in which each carbon is optionally substituted by one or two alkyl groups of Ca. Suitable substituents for ρr are 1, or favorably, 2 alkoxy groups, especially methoxy groups, and the substituents being favorably bonded in the 3- and 4- positions relative to the point of attachment of the Rr to the variable R. Preferably, Ar represents 3, -dimethoxy phenyl. Suitably, R represents a n-alkylene group of unsubstituted C _ *. Preferably, fl represents -CHja-CHa. When R is alkyl it is preferably a Ca-alkyl. such as alkyl of Ca <; C3 alkyl, C alkyl, Cs alkyl or C <1> alkyl; & In one aspect, Rx is alkylene or cycloalkyl. Preferably, R is hydrogen. Suitably, any of Ra, Ra and R represents nitro and the remaining members of the group of Rs », Ra and R represent hydrogen. Preferably, Ra represents 4-nitro. Preferably, Ra and F each represent hydrogen. Suitably, Z represents an n-alkylene group of Ca-. unsubstituted Suitably, Z represents CH2CH2CHa > . A compound of particularly preferred formula is N-C3-CC2- (3,4-dimethoxyphenyl) ethyl-3-amino-1-propyl] -4-nitro-benzene or a salt thereof, such as a hydrochloride salt or a solvate thereof. As used herein, and unless otherwise indicated, the term "alkyl" includes straight or branched chain alkyl groups having from 1 to 12, favorably 1 to 6 carbon atoms and will include such alkyl groups when forming part of other groups such as alkoxy or arylalkyl groups.

As used herein, the term "alkylene" includes straight or branched chain alkylene groups having from 2 to 12, favorably 2 to 6 carbon atoms. As used herein, the term "cycloalkyl" includes cycloalkyl groups of C3-βJ favorably carbon- Ca groups. As used herein, and unless otherwise indicated, the term "aryl" includes phenyl and naphthyl, preferably phenyl. As used herein, and unless otherwise indicated, the term "halogen" includes fluorine, chlorine or bro. As used herein, the term "cardiac arrhythmia" refers to any variation of the normal rhythm of the heartbeat, including, without limitation, breast arrhythmia, premature heartbeat, heart block, fibrillation, flutter, tachycardia, paroxysmal tachycardia. and premature ventricular contractions. The compounds of formula (1) may possess a chiral carbon atom (for example when Z represents a branched alkylene group and may therefore exist in more than one stereoisomeric form.The invention is extended to any of the stereoisomeric forms, including The various stereoisomeric forms can be separated or resolved one from the other using conventional methods or any given isomer can be obtained by conventional stereospecific or asymmetric syntheses. Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable mineral acids such as hydrochloric, hydrobromic, boric, phosphoric, sulfuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic acids. , benzoic, ascorbic, methanesulfonic, α-keto-glutaric, Gigueerofosfórico and glucose-1-phosphoric. Preferably the acid addition salt is a hydrochloride. Pharmaceutically acceptable salts include pharmaceutically acceptable N-oxides and the invention extends to these. The compounds of the formula (I) and their salts can also form sols, especially pharmaceutically acceptable solvates, such as hydrates, and the invention is extended thereto, especially pharmaceutically acceptable solvates. The salts and / or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable, may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of the formula (I) or the compounds of the formula (I) themselves , and as such form one aspect of the present invention.

A compound of formula (I) or a salt thereof or a solvate thereof, can be prepared by reacting a compound of formula (II): where A, Rr, Ra. and Z are as defined in relation to formula (I), with a compound of formula (III): wherein Ra, Ra and R are as defined in relation to formula (I) and La. represents a starting group; and subsequently, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into an additional compound of formula (I); (ii) preparing a salt of the compound of formula (I) and / or a pharmaceutically acceptable solvate thereof. The compounds of formula (III) are known and commercially available compounds. The reaction between the compounds of the formulas (II) and (III) can be carried out in any inert solvent, such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamin, at a temperature that provides a suitable speed of formation of the required product, generally at a low to ambient temperature, preferably ambient. A starting group La. preferred is a halogen atom, such co or chlorine atom. The compounds of formula (II) are known compounds and can be prepared by the method described in Offenlegungsschrift 2345423. The compounds of formula (II) can also be prepared by reducing a compound of formula (IV): av) wherein A, Ar and R are as defined in relation to the compound of formula (I) and Z represents an n-alkylene group of C a in which each carbon is optionally substituted by an alkyl group of CX_ ?. The reduction of the compounds of formula (IV) can be carried out using conventional reducing agents and conditions, for example, using a metal hydride reducing agent, such as lithium aluminum hydride, in an aprotic solvent such as tetrahydrofuran or diethyl ether or mixtures thereof, at a temperature that provides an adequate rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent. The compounds of formula (IV) can be prepared by reacting a compound of formula (V) H N-A -Ar (V) wherein A, Ar and R are as defined in relation to the compound of formula (I), with a compound of formula (VI): H2N-CO-Z ^ j (VI) wherein Z is as defined in relation to the compound of formula (IV) and La represents a starting group. The reaction between the compounds of formulas (V) and (VI) is carried out in an aprotic solvent, such as acetonitrile, at a temperature which provides an adequate rate of formation of the required product, generally at an elevated temperature and conveniently at reflux temperature of the solvent; preferably the reaction is carried out in the presence of a base, usually an organic base such as trialkyl amine, for example triethylamine or a complex such as potassium fluoride in celite (Takashi Ando, 3unko Yamawaki, Chemisty Letters, 1979, p. Four. Five). A preferred starting group L 'is a halogen atom, such as a chlorine atom. The compounds of formula (V) are known and commonly available compounds. The compounds of formula (VI) are known compounds or are prepared using methods analogous to those used to prepare known and commercially available compounds. In a further aspect, the invention provides a process for the preparation of a compound of formula (I), which comprises demethylating a compound of formula (VID: wherein A, Ar, R ", Ra, *, X and Z are as defined in relation to the compounds of formula (I); and subsequently, if required, converting any portion -NH- thus formed into an NRa group in which Rs represents alkyl of Ca, an alkenyl or a cycloalkyl group. The demethylation of the compounds of formula (VII) can be affected using any conventional demethylation method, for example by using the methods described in 3. Org. Chem., 1975, 40, 1850, ibid, 1984, 49, 2081 or those methods described in Synthesis 1991, 318. The conversion of any portion -NH- into a group NR5 in which R5 represents an alkyl of Cas_? an alkenyl or a cycloalkyl group can be carried out using conventional methods of alkylation, alkenylation or cycloalkylation, by the use of the appropriate alkylhalogenide, alkenylhalogenide or cycloalkylhalide, suitably an iodide in the presence of a base such as potassium bicarbonate in an aprotic solvate such as tetrahydro uran. In a further aspect, the invention provides a compound of formula (VID or a salt thereof or a solvate thereof as an intermediate) A compound of formula (I) or a salt thereof or solvate thereof, can be prepared also bringing to reaction a compound of formula (VIII): wherein R2, Ra, R. "., X and Z are as defined in relation to formula (I) and La is a starting group such as halogen, with a compound of formula (IX): wherein A, Ar and R are as defined in relation to formula (I); and subsequently, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into an additional compound of formula (I); (ii) preparing a salt of the compound of formula (I) and / or a pharmaceutically acceptable solvate thereof. The reaction between the compounds of formulas (VIII) or (IX) can be carried out in any suitable inert solvent, such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamine, at a temperature that provides an adequate rate of formation of the required product, generally at a high temperature, such as the reflux temperature of the solvent. A suitable value for La is chlorine. A compound of formula (VIII) ee can be prepared by the reaction between a compound of formula (III) defined above and a compound of formula (X): HzN-Z-La (X) wherein Z is as defined in relation to formula (I) and La is as defined in relation to the formula (VID) The reaction between the compounds of formulas (III) and (X) can be carried out under conventional acylation conditions, for example in an inert solvent such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamine, at a temperature that provides an adequate rate of formation of the required product, generally at a low ambient temperature, preferably at room temperature. The compounds of the formula (X) are known and commercially available compounds A suitable conversion of a compound of the formula (I) in an additional compound of formula (I) includes the interconversion of variable R in the compounds of formula (I), for example, the conversion of compounds in which R is H into compounds of formula (I) in which R represents alkyl, suitably C alquilo ~ alkyl & , alkenyl or cycloalkyl or the aforementioned conversion of the compounds wherein R is methyl in co p? estoe in which R is hydrogen, alkyl, alkenyl or cycloalkyl. It will be appreciated that in any of the reactions and conversions mentioned above any reactive group in the substrate molecule can be protected, in accordance with conventional chemical practice. The methods of forming and removing such protecting groups are those conventional methods appropriate for the molecule being protected. As mentioned above, the compounds of the invention are indicated as possessing useful therapeutic properties: the present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, for its use as an active therapeutic substance. More particularly, the preeente invention provides a compueeto of formula (I) ou ^ a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof for use in the treatment and / or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia and also ischemic rhythm disorders. 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, co or a pharmaceutical composition also consisting of a pharmaceutically acceptable carrier. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the general formula (I) or a pharmaceutically acceptable salt of the same or a pharmaceutically acceptable eolvate thereof and a pharmaceutically acceptable carrier therefor. A compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof is usually administered in unit dosage form. An amount effective to treat the disorder described above in the present depends on factors such as the efficacy of a compound of formula (I), the particular nature of the pharmaceutically acceptable salt or the pharmaceutically acceptable solvate chosen, the nature and severity of the disorders that are being treated and the weight of the mammal. However, a unit dose will usually contain 0. 1 to 500 mg for example 2 to 50 g, of the compound of the invention. Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more commonly 2 to 4 times a day, so that the total daily dose is normally on the scale, for an adult of 70 kilos, from 0.1 to 2500 mg, more commonly from 1 to 1000 ing, for example 1 to 200 mg, ie on the scale of approximately 0.02 to 3 rng / kg / day, very commonly from 0.1 to 3 ng / kg / day, for example from 0.15 to 2 mg / kg / day. In the dosing scale described above, no toxicological effects are indicated for the comp-estoe of the invention. In such treatment, the coetate can be administered by any suitable route, e.g., by oral, parenteral or topical routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a human or veterinary pharmaceutical carrier, diluent and / or excipient, although the exact form of the composition will naturally depend on the mode of administration. The compositions are prepared by mixing and are suitably adapted for oral, parenteral or topical administration, and as such may take the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable solutions or suspensions or infusion, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular orally shaped compositions, since these are more convenient for general use. Tablets and capsules for oral administration are commonly presented in a unit dose and contain conventional excipients such as binding agents, binders, diluents, tablet-forming agents, lubricants, disintegrants, colorants, flavors and wetting agents. Lae tablets can be coated according to methods well known in the art. Suitable renderers for use include cellulose, anitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable and pharmaceutically acceptable wetting agents include sodium? Rilsylphosphate. Solid oral compositions can be prepared by conventional methods of mixing, filling, tapping or the like. Repeated mixing operations can be used to distribute the active ingredient through those compositions using large amounts of fillers. Such operations are, of course, conventional in the art. Oral liquid preparations may be in the form of, for example, suspensions, solutions, emulsions, aqueous or oily syrups or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils, emulsifying agents, for example lecithin, sorbitan nonooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavoring or coloring agents. For parenteral administration, unit fluid dosage forms containing a compound of the present invention and a sterile vehicle are prepared. The compound, depending on the vehicle and concentration, can be either dissolved or dissolved. Parenteral solutions are usually prepared by dissolving the active compound in a vehicle and filter sterilizing before filling in a suitable vial or vial and sealing. AdvantageouslyAdjuvants such as local anesthetics, preservadore and pH regulating agents are also dissolved in the vehicle. To improve the stability, the composition can be frozen before filling it into the bottle and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being distylated and sterilized by exposure to ethylene oxide before suspending it in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate the uniform distribution of the active compound. For topical administration, the composition may be in the form of an ointment or transdermal patch for the systematic release of the compound and may be prepared in a conventional manner, for example, as described in standard textbooks such as "Dermatological Formulactions" -BU Barry (Drugs and the pharmaceutical Sciences - Dekker) or Harrys Cos eticology (Leonard Hill Books). In addition, such compositions may contain additional active agents such as hypertensive agents and diuretics. As is common practice, the compositions will normally be accompanied by written or printed instructions for s? Use in related medical treatment. As used herein, the term "pharmaceutically acceptable" encompasses compounds, compositions and ingredients for both human and veterinary use: for example the term "pharmaceutically acceptable salt" encompasses a veterinarily acceptable salt. The present invention additionally provides a method for the treatment and / or prophyxis of the arrhythmia, especially cardiac arrhythmia, such as ventricular arrhythmia, and also disorder of the ischemic rhythm in a human or non-human mammal, which consists of administering a effective and non-toxic amount of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof to a human or non-human mammal in need thereof. Conveniently, the active ingredient can be administered as a pharmaceutical composition defined hereinbefore, 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 the general formula (I) or a pharmaceutically acceptable salt thereof and / or pharmaceutically acceptable solvate thereof can be taken in dose as those previously described. Similar dosage regimens are suitable for the treatment and / or prophylaxis of non-human mammals. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia and also ischemic rhythm disorders. No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable salt of the same or a pharmaceutically acceptable solvate thereof is administered at the aforementioned dosage scales. The following descriptions and examples illustrate the invention but do not limit it in any way. Figure 1 shows the effect of the compound of Example 1 on the action potential duration (RPD) recorded in guinea pig papillary muscle. Figure 2 shows the effect of Example 2 on the duration of the action potential measured at 30% repolarization (RPD30) and at 90% repolarization (RPD90) in isolated guinea pig papillary muscle.

DESCRIPTION 1 3-CC2-Í3, 4-Dimeto ifenil) ethyl] metilami or] propanesaride 6. 42 g (60 mmol) of 3-chloropropanamide, 5.85 g (30 mmol) of N-methyl-3,4-dimethoxybenzeneethanamine and 7.7 g (75 mmol) of tritylene ina in 100 mL of acetonitrile were stirred under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel using rnetylene chloride / methanol: 92/8 to yield 5.12g (64.1%) of the desired compound as an orange oil. H NMR (CDC13) 6 = 2.40 (s, 3H; NCH3); 2.46 (t, 2H, 3 = 5.9Hz, CHa); 2.74-2.79 (m, 6H, 3CH2); 3.85 and 3.87 (2s, 6H, 2CHa0); 6.70-6.78 (m, 3H, 3Ar); 7.71 (broadband, 2H, interS DasO, NHa-) ppm.

DESCRIPTION 2 N- C2- (3, -dimethoxy phenyl) ethyl] -N-rnethyl-1,3-propanediarine 1. 5 g (5.6 mmoles) of 3-CC 2- (3,4-dimethoxy phenyl) ethyl] -methylamino] propanamide (DI) in dry tetrahydrofuran was added dropwise to a suspension of 0.64 g (1.7 mmol) of aluminum hydride. lithium in 20 ml of dry diethyl ether by stirring. The mixture was heated under reflux for 2 hours and then cooled with an ice water bath before carefully adding 0.65 ml of water 0.65 ml of 15% aqueous NaOH and then 1.95 ml of water by dripping. The mixture was dried over MgSO 4, concentrated in vacuo and the residue was purified twice by basic alumina chromatography using methylene chloride / methanol: 95/5, followed by ethylene chloride / methanol / 30% aqueous ammonia: 90/10 /0.1 to produce 0. 86g (60.8%) of the desired compound. 7"? XH NMR (CDCl3 d = 1.65 (m, 2H, CHa); 2.15 (broad band, 2H interc Ds ^ NHs,); 2.30 (s, 3H, NCHa); (t, 2H, 3 '= 7.4Hz, CHa); 2.53-2.79 (rn, 6H, 3CH2); 3.85 and 3.87 (2s, 6H, 2CHaO); 6.71-6.82 (m, 3H, 3Ar)? Pm.

DESCRIPTION 3 N- (3-Chloropropyl) -4-nitrobenzarnide or N • 'k, .Cl A solution of 6.43 g (49 mmol) of 3-chloropropylamine and 13.6 ml (98 mmol) of triethylamine in 220 ml of ethylene chloride was cooled by an ice bath and 9 g (48.5 mrnol) of 4-fold chloride were added. -nitrobenzoyl. After one hour of stirring at room temperature the organic phase was washed twice with water, dried over MgSO * and concentrated in vacuo to yield 10.68g (91%) of beige crystals. The XH NMR was consistent with the desired structure.

EJEflPLO I N- [3-CC2- (3,4-dimethoxyphenyl) ethyl] methy1] mino] propyl] -4-nitrobenza ida hydrochloride 800 mg (3.17 mmol) of N-C2- (3,4-dimethoxyphenyl) ethyl] -N-rnethyl-1,3-propanediarine (D2), 630 mg (3.33 mmol) of 4-nitrobenzoyl chloride and 0.35 g ( 3.49 mmole) of triethylamine in 30 ml of methylene chloride were stirred for two hours at room temperature. The mixture was washed with water, dried over MgSO * and concentrated in vacuo. The residue was purified twice by silica gel chromatography using ethylene / methanol chloride: 97/3 then 94/6 yielding 700 mg (55%) of the desired compound as a base. The compound was purified in methylene chloride by adding a hydrochloric acid solution in diethyl ether yielding 594 mg (43%) of the extracted compound as a yellow solid: mp = 80-90 ° C. X H NMR (DMSO-d?) D = 2.00 (m, 2H, CHa); 2.79 (8.3H, NCHa); 2.90 (m, 2H, CHZ); 2.95 (m, 2H, CHa); 3.20 (m, 2H, CH2); 3.35 (m, 2H, CH2, 3.72 and 3.74 (2s, 6H, 2CHa0), 6.80-6.96 (M, 3H, flr), 8.12 (d2H, 3 = 7.9Hz, Ar), 8.33 (d, 2H, 3 = 7.9Hz, Ar), 9.05 (broad band, lH, interc Ds.O, NH), 10.45 (broadband, 1H, interc DaO, NH) ppm.

EXAMPLE 2 N-C3-CC2- (3,4-dimethoxyphenyl) ethyl] -amino] propyl] - 4-nitrobenzamide hydrochloride A solution of 10.62g (44 mmoles) of N ~ (3-chloropro-yl) -4-nitrobenzamide (D3), 8.1g (45 mmoles) of homoveratrila ina and 6.26 ml of triethylamine in 200 ml of methylene chloride were taken reflux for 48 hours. The solvent was subsequently concentrated under vacuum and the residue dissolved in water. The aqueous phase was washed first with methylene chloride, then made basic with aqueous NaOH and finally extracted twice with rnetylene chloride. This second organic phase was dried over MgSO and concentrated in vacuo yielding 12g of crude residue. This residue was purified by chromatography on silica gel using CHaCls./MeOH/NH.vOH:85/10/5 to yield 4.4g of the title compound as a yellow oil (free base). This compound was dissolved in methanol and acidified by anhydrous hydrogen chloride solution in diethyl ether yielding after drying 4.4g of the title compound as pale beige crystals, mp: 14I-2 ° C XH NMR (DMSO-d6) or = 1.93 (, 2H, CHJ2); 2.89-3.16 (m. «_ H.3 ~ cH =.); 3.40 (m, 2H, CHa); 3.72 and 3.75 (2s, 6H, 2xOCHa); 6.74-6.91 (m, 3H, Ar); 8.12 (d, 2H, J = 8.6Hz, Ar); 8.32 (d, 2H, 3 = 8.6Hz, Rr); 9.12 (broadband, 2H, inter DaO, NHa +) 9.15 (t, lH, INTERC DaO, NH) pprn PHARMACOLOGICAL DATA Methodology Guinea pigs (300-350g) were anaesthetized by intravenous injection of sodium pentobarbital (60 mg / kg). After the thoracotomy the heart was quickly excised and placed in an oxygenated Tyrode solution. The papillary muscles of the right ventricle were removed. The preparations were then fixed to the silastic base of an organ bath of 5 ml and superfused with oxygenated Tyrode solution maintained at 37 + 1 ° C. The modified Tyrode solution (pH 7.35) contained the following (mM): NaCl 125, KCl 4.0, MgCla 0.5, CaCla 1.8, NaHCOa 24, NaHsaPO. " 0.9 and glucose 5.5. The solution was equilibrated with a gas mixture of 95% 0a - 5% C0a. After a period of stabilization (at least lh), the transmembrane action potentials were recorded with conventional microelectrodes (10 MOhm) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were supplied to the preparation with bipolar platinum electrodes placed at one end of the muscle. The pulse duration was 1 ms and the amplitude was twice initiated. The length of the basic cycle was 1000 s (PULSAR stimulator 6i). The signals were monitored on a storage oscilloscope (GOULD 1602) and recorded simultaneously on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis. Measurements of the amplitude of the action potential (RPR) and of the action potential durations were made at 30 and 90% repolarization (APD30 and RPD90 respectively). The records were made after 30 minutes of equilibration for each concentration. Only the records in which the same impalement was maintained throughout the experiment were used for the analysis.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS
1. A compound of formula (I) (D) or a salt thereof or solvate thereof, further characterized in that: Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms, any two substituents together with the carbon atoms to which they are attached can form a fused heterocyclic ring of five to six atoms in which one, two or three of said atoms are oxygen or nitrogen; A represents a n-alkylene group of C; wherein each carbon is optionally substituted by one or two alkyl groups of C- ?; Rx represents hydrogen, alkyl, alkenyl or cycloalkyl, one or two of the group of Ra, Ra and R represents nitro and the remaining members of the group of Rz, Ra and R * represent hydrogen, X represents a -CO-NH- moiety, and Z represents an n-alkylene group of Ca- ^ in which each carbon is optionally substituted by one or two alkyl groups of C - «s.
2. 2. - A compound according to claim 1, wherein Ar represents a substituted or insituted phenyl group.
3. 3. A compound according to claim 1 or claim 2, wherein Ar represents a phenyl group substituted with one or two alkoxy groups.
4. 4. A compound according to any of claims 1 to 3, wherein R represents hydrogen, alkyl, alkenyl or cycloalkyl.
5. 5. A compound according to any of claims 1 to 4, wherein R is hydrogen.
6. 6. A compound according to any of claims 1 to 5, wherein one of Ra, Ra and R represents nitro and the remaining members of the group of Ra, a and F represents hydrogen.
7. 7. A compound according to claim 6, wherein Ra represents 4-nitro and Ra and R each represent hydrogen.
8. 8. A compound according to any of claims 1 to 7, wherein Z represents CHaCHaCHa.
9. 9. A compound according to claim 1, which is N-C3-CC2- (3,4-dimethoxyphenyl) ethyl] amino] propyl] -4-nitrobenzamide; or a salt thereof, or a solvate thereof.
10. 10. A process for preparing a compound of formula (I) as defined in claim 1, or a salt thereof, or a solvate thereof, which process comprises: carrying a compound of formula (II) wherein fl, flr, R and Z are as defined in relation to formula (I), with a compound of formula (III): wherein Ra, Ra and R * are as defined in relation to formula (I) and L represents a starting group; or (ii) demethylating a compound of formula (VID: wherein 0, Ar, Ra, Ra, *, X and Z are as defined in relation to the compounds of formula (I); and subsequently, if required, converting any portion -NH- thus formed into a group NRS in which R "represents alkyl of Cs._ ?, an alkenyl or a cycloalkyl group; or (iii) reacting a compound of formula (VIII): wherein Ra, R3, R *, X and Z are as defined in relation to formula (I) and L.a is a starting group, such as halogen, with a compound of formula (IX): HN-A -Ar (IX) wherein A, Ar and R are as defined in relation to formula (I); and subsequently carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into an additional compound of formula (I); (ii) preparing a salt of the compound of formula (I) and / or a pharmaceutically acceptable solvate thereof.
11. 11. A pharmaceutical composition consisting of a compound of formula (D as defined in claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier. of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable eolvate thereof, for the manufacture of a medicament for the treatment and / or prophylaxis of arrhythmia and trachea of ischemic rhythm in a human or non-human mammal.