WO1995007884A1

WO1995007884A1 - Alkanediamine derivatives and their use in the treatment of arrhythmic and ischaemic rhythm disorders

Info

Publication number: WO1995007884A1
Application number: PCT/EP1994/002959
Authority: WO
Inventors: Guy Marguerite Marie Gérard NADLER; Michel Jean Roger Martin
Original assignee: Smithkline Beecham Laboratoires Pharmaceutiques
Priority date: 1993-09-13
Filing date: 1994-09-05
Publication date: 1995-03-23
Also published as: TW274083B; ZA946989B; FR2710059A1; AU7694394A

Abstract

A compound of formula (I) or a salt thereof, or a solvate thereof, wherein A and B each independently represents a C1-4 n-alkylene group wherein each carbon is optionally substituted by a C1-6 alkyl group; D represents CO, SO2, NH-CO or CH2CO; T represents hydrogen, alkyl, alkenyl or cycloalkyl; Z represents a bond, CH2, (CH2)2 or X-CH2-CH2 wherein X represents O or S; R1, R2 and R3 each independently represents H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of R1, R2 and R3 together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; R4 represents alkylsulphonamido, alkylamido or imidazo; and Ar represents substituted or unsubstituted aryl, wherein the optional substituents are the above defined R1, R2 and R3; a composition containing such a compound, a process for the preparation of such a compound and the use of such a compound in medicine.

Description

Al aned1am1ne derivatives and their use 1π the treatment of arrhythmic and 1 schaem1c rhythm di sorders

The invention relates to certain novel compounds, to pharmaceutical 5 compositions containing such compounds, to a process for the preparation of such compounds and to the use of such compounds as active therapeutic agents. EP 0233 762 discloses a class of compounds of formula A

?2 R₃ I I ³

R— N-A-N-B — R₄ 10 (A) wherein:

R and R4 are independently phenyl optionally substituted by one, two or three of halogen, trifluoromethyl, Cj.4 alkoxy, C\._ alkyl, cyano, hydroxy, nitro, NR5 R6 or O2SNR5 R wherein R5 and R5 are independently hydrogen or Cj.g alkyl or together

15 are C3.6 polymethylene, or disubstituted at adjacent carbon atoms by C1--2 alkylenedioxy and optionally further substituted by one of the above groups; R2 is selected from (CH2)_Z CN where z is zero or an integer from 1 to 4, Cj_i2 alkyl, C3.7 cycloalkyl, C3-.7 cycloalkyl C\._\ alkyl, phenyl C1-.4 alkyl, pyridyl, pyridyl C1-.4 alkyl, COR₇', COCH₂COR₇', SO2R7', CO2R7', CONHR₇' and CSNHR₇', where R₇' is

20 selected from C3- 2 alkyl, C3-.7 cycloalkyl, C3-.7 cycloalkyl C1-.4 alkyl, phenyl and phenyl C\._\ alkyl, any alkyl moiety in R7 optionally substituted by hydroxy or C1-.4 alkanoyloxy, any pyridyl or phenyl moiety in R2 optionally substituted as defined for W\ and R4 and any cycloalkyl moiety in R2 optionally substituted by one or two C1-.4 alkyl groups;

25 R3 is hydrogen or C 1.4 alkyl; A represents C2-5 alkylene; and B represents C}_4 alkylene.

These compounds are stated to possess cardiovascular activity, in particular calcium antagonistic activity which indicates that they are of potential use in the

30 treatment of angina pectoris. In WO 93/23024 ceπain of the compounds of formula (A) are disclosed as having both class III and class IV antiarrhythmic activity.

It has now been discovered that ceπain novel aromatic diamines show evidence of prolongation of cardiac action potential and are therefore considered to show particular promise as anti-arrhythmic agents particularly in the treatment of ventricular arrhythmias

35 Accordingly, the invention relates to a compound of formula (I):

(I)

or a salt thereof, or a solvate thereof, wherein

A and B each independently represents a C\._ n-alkylene group wherein each carbon is optionally substituted by a C\. alkyl group; D represents CO, SO2, NH-CO or CH₂CO; T represents hydrogen, alkyl, alkenyl or cycloalkyl; Z represents a bond, CH2, (CH2>2 or X-CH2-CH2 wherein X represents O or S;

R\, R2 and R3 each independently represent H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of R\, R2 and R3 together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; R4 represents alkylsulphonamido, alkylamido or imidazo; and

Ar represents substituted or unsubstituted aryl, wherein the optional substituents are the above defined R\, R2 and R3

Suitably, A represents (CH2)3. Suitably, B represents CH2CH2. Suitably, D represents CO, SO2 or NH-CO or CH2CO.

Suitably, T represents CH3

Suitably, one or two of R\, R2 and R3 represents alkoxy, for example methoxy, the remaining member(s) being H.

Suitably, R\, R2 and R3 each independently represents hydrogen. Examples of R4 include methylsulphonamido, acetamido and 1 -imidazo, suitably the substituent is attached at the 4-position on the phenyl ring.

As used herein, unless indicated to the contrary, the term "alkyl" includes straight or branched chain alkyl groups having from 1 to 12, favourably 1 to 6, carbon atoms and shall include such alkyl groups when forming paπ of other groups such as alkoxy or arylalkyl groups.

As used herein, unless indicated to the contrary, the term "alkenyl" includes straight or branched chain alkylene groups having from 2 to 12, favourably 2 to 6, carbon atoms and one or more double bonds. As used herein, unless indicated to the contrary, the term "aryl" includes phenyl and naphthyl, preferably phenyl.

As used herein, unless indicated to the contrary, the term "cycloalkyl" includes C3-g preferably C3-.6 cycloalkyl groups. As used herein "halogen" includes fluorine, chlorine or bromine.

As used herein, the term "cardiac arrhythmia" relates to any variation from the normal rhythm of heaπ beat, including, without limitation, sinus arrhythmia, premature heaπbeat, heaπblock, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions. The compounds of formula (I) may possess chiral carbon atoms and therefore may exist in more than one stereoisomeric form. The invention extends to any of the stereoisometric forms, including enantiomers of the compounds of formula (I) and to mixtures thereof, including racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.

The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable mineral acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, taπaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α- keto-glutaric, α-glycerophosphoric, and glucose- 1 -phosphoric acids. Preferably the acid addition salt is a hydrochloride.

Pharmaceutically acceptable salts also include quaternary salts. Examples of quaternary salts include such compounds quaternised by compounds such as R^z-T wherein R^z is C\. alkyl, phenyl-Ci.g alkyl or C5.7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R^z include methyl, ethyl and n- and iso- propyl; and benzyl and phenethyl. Suitably T includes halide such as chloride, bromide and iodide.

Pharmaceutically acceptable salts also include pharmaceutically acceptable N- oxides, and the invention extends to these. The compounds of the formula (I) and their salts may also form solvates, especially pharmaceutically acceptable solvates, such as hydrates, and the invention extends to these, and especially to the pharmaceutically acceptable solvates.

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

A compound of formula (I) or a salt thereof, or a solvate thereof, may be prepared by reacting a compound of formula (II):

(ID

wherein A, B, T, Z, Rj , R2, R3 and Ar are as defined in relation to formula (I) with a compound of formula (III);

(HI) wherein R5 is R4 as defined in relation to formula (I) or a group convertible into R4, providing that:

(a) for the preparation of compounds of formula (I) wherein D is CO, CH2CO or SO2, X represents CO-Lj, CH2CO.L1 or SO2 1 respectively, wherein L\ is a leaving group or atom, such as a halogen atom; or (b) for the preparation of compounds of formula (I) wherein D is NH.CO, X is

N=C=O; and thereafter, if required, carrying out one or more of the following optional steps:

(i) for compounds wherein R5 is not R4, converting R5 into R4; (ii) converting a compound of formula (I) into a further compound of formula (I); (ii) preparing a salt of the compound of formula (I) and/or a solvate thereof.

Suitably, when R4 in the required compound of formula (I) is imidazo, R5 is imidazo.

Suitably, when R4 in the required compound of formula (I) is alkylsulphonamido or alkylamido, then R5 is alkylsulphonamido or alkylamido respectively or as described below R5 may be a group convertible into R4.

Suitable groups convertible into alkylsuphonylamido or acylamido groups are amino groups, preferably in protected form, or groups which are readily converted into amino groups without affecting the rest of the molecule, such as nitro groups.

When R5 is a protected amino group or a group which is readily converted into an amino group, such group is first converted into an amino group and the amino group so formed is then converted into the required alkylsulphonamido or alkylamido group, conveniently, by reaction with a compound of formula (IV):

R₆-L₂ (IV) wherein Rg represents C\. alkylSθ2- or Cj.g alkylCO- and L2 is a leaving group or atom, such as a halogen atom.

The reaction conditions for the reaction between the compounds of formula (II) and either the compound of formula (III) or of formula (IV) are conventional conditions appropriate to the nature of the reagent used, generally however the reaction may be carried out in an ineπ solvent, such as methylene chloride, at any suitable temperature providing a convenient rate of formation of the desired product, generally at an ambient to elevated temperature, conveniently at the reflux temperature of the solvent and preferably in the presence of a base such as triethylamine. Suitable amino protecting groups include those used in peptide synthesis, such as carbamate groups. The deprotection of amino groups may be carried out using any conventional procedure.

When R5 is a group which is readily converted into an amino group, such group is converted into an amino group using using any appropriate method: Thus when R5 is nitro, the nitro group may be converted into an amino group by conventional reduction methods, for example by using a stannous salt such as stannous chloride in an alkanolic solvent, such as ethanol, at any suitable temperature providing a convenient rate of formation of the desired product, generally at an ambient to elevated temperature, conveniently at the reflux temperature. Compounds of formula (II) are known compounds or they may be obtained by procedures analogous to those used to prepare known compounds, for example as described in EP 0 233 762.

The compounds of formula (III) are known commercially available compounds - fo example those wherein X represents CO.Cl or SO2.CI and R5 is NO2 - or they may be obtained by procedures analogous to those used to prepare known compounds, for example compounds of formula (III) wherein X represents CO.Lj or CH2COL1 may be prepared according to methods described in Organic Synthesis, Coll. Vol. I page 394 or

Organic Synthesis, Coll. Vol. Ill, page 29, compounds of formula (III) wherein X represents SO2. 1 may be prepared according to methods described in Organic Synthesis, Coll. Vol. VIII, page 104 and for compounds of formula (III) wherein X represents N=C=O according to methods described in Organic Synthesis, Coll. Vol. Ill, page 846.

The compounds of formula (IV) are known commercially available compounds. It will be appreciated that in any of the abovementioned reactions any reactive group in the substrate molecule may be protected, according to conventional chemical practice. Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.

As mentioned above the compounds of the invention are indicated as having 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 use 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, for use in the treatment of and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischeamic rhythm disorders.

A compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered rjer ££ or, preferably, as a pharmaceutical composition also comprising 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 thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier thereof.

A compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage form.

An amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of a compound of formula (I) , the particular nature of the pharmaceutically acceptable salt or pharmaceutically acceptable solvate chosen, the nature and severity of the disorders being treated and the weight of the mammal.

However, a unit dose will normally contain 1 to 50 mg for example 2 to 15 mg, 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 usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 300 mg, more usually 4 to 100 mg, for example 10 to 60mg, that is in the range of approximately 0.02 to 5 mg/kg/day, more usually 0.1 to 2 mg/kg/day, for example 0.1 to 0.5 mg/kg/day.

In such treatment, the compound may be administered by any suitable route, e.g. by the 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. Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or 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, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium 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 esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial 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 dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included 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 systemic delivery of the compound and may be prepared in a conventional manner, for example, as described in the standard textbooks such as 'Dermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences - Dekker) or Harrys Cosmeticology (Leonard Hill Books).

In addition such compositions may contain further active agents such as anti-hypertensive agents and diuretics.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned. As used herein the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.

The present invention further provides a method for the treatment and/or prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular arrhythmia, and also ischemic rhythm disorders in a human or non-human mammal which comprises administering an effective, 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 may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

In the treatment and/or prophylaxis of arrhythmia and/or ischeamic arrhythmia disorders the compound of the general formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above.

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.

The following Examples illustrate the invention but do not limit it in any way. Description 1

4-Amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxypheny|)ethyI]methylaminυ] propyl]benzamide, dihydrochloride.

A mixture of 1.12 g (2.0 mmol) of N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyl) ethyl]methylamino]propyl]-4-nitrobenzamide hydrochloride (described in, EP 233 762) and 2.25 g (10 mmol) of stannous chloride dihydrate in 15 ml ethanol were refluxed under stirring for 30 minutes. The solvent was concentrat-ed to dryness and the residue taken up in water. The aqueous mixture was basifϊed with an aqueous solution of NaHCO3 and extracted three times with ethyl acetate. The organic solution was separated, dried over M SO4 and concentrated in vacuo to dryness. The crude base (0.88 g) was taken up in methanol and a solution of 5.5N anhydrous HCl in diethyl ether was added. The main part of the solvent was removed under reduced pressure and anhydrous diethyl ether was added to precipitate the desired dihydrochloride : 0.89 g (77%). m.p = 135-40°C *H NMR(DMSO-d₆) δ = 1.82-2.04 (m,2H,CH₂): 2.78 (d,3H,J=4.3Hz,CH₃NH); 2.86- 2.99 (m,2H,CH₂); 3.04-3.37 (m,4H,2CH₂); 3.66, 3.69, 3.72 and 3.75 (4s,12H,4CH₃O); 3.78-3.94 (m,2H,CH₂); 6.60-6.93(m,8H,Ar); 7.16 (d,2H,J=8.4Hz,Ar); 10.36 (s,lH,exchD₂O,NH+) ppm

Description 2

N-(3,4-DimethoxyphenyI)-N-[3-[[2-(3,4- dimethoxyphenyI)ethyI]methylamino]propyI]-N-(4-nitrophenyl)urea, hydrochloride

A solution of 1 g (2.6 mmol) of N-(3-4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl)ethyl]-N'-methyl-l,3-propanedimamine and 0.48 g (3 mmol) of 4- nitrobenzeneisocyanate in 25 ml dry methylene chloride was stirred at room temperature for 15 hours. The precipitate was filtered and purified by chromatography on silica gel using 95:5 methylene chloride:methanol yielding 0.83 g of a yellow solid which was salified in methanol by addition of 5.5N anhydrous HCl in diethyl ether. The crude salt was triturat-ed in diethyl ether to afford 0.8 g (55.7%) of a^'yellow solid, m.p around 115°C ^lH NMR (DMSO-d₆) 5 = 1.80-1.98 (m,2H,CH₂); 2.78 (d,3HJ=4.5Hz,CH₃NH⁺); 2.86- 3.02 (m,2H,CH₂); 3.08-3.43 (m.4H,2CH₂); 3.68-3.87 (m,2H,CH₂); 3.72, 3.74, 3.77 and 3.79 (4s,12H,4CH₃O); 6.72-7.07 (m,6H,Ar); 7.76 (d,2HJ=9.3Hz,Ar); 8.12 (d,2H,J=9.3Hz,Ar); 8.48(s,lH,exch.D₂O,NH); 10.27(broad s,lH,exch.D₂O,NH+)ppm.

Example 1

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl]ethyl] methylamino]propyI]-4-(methylsuIphonylamino)-beπzenesuIphonamide hydrochloride.

To a stirred solution of 1 g (2.6 mmol) of N-(3,4-dimethoxyphenyl)-N'-[3-[[2-(3.4- dimethoxyphenyl]ethyl]-N'-methyl-l,3-propanediamine and 0.26 g (2.6 mmol) of triethylamine in 30 ml of chloroform, 0.7g (2.6 mmol) of 4-(methylsulphonylamino) benzenesulphonyl chloride were added dropwise and the mixture was stirred at room temperature overnight.

50 ml of methylene chloride were added and the organic phase was washed three times with 50 ml water, dried over MgSO4 and concentrated in vacua Purification by flash chromatography on silica gel using 80:10:10 ethyl acetate : methylene chloride : ethanol yielded 0.52 g of product. This was further purified by flash chromatography on silica gel using 95:5 ethyl acetate : methanol to afford 0.43 g (0.6 mmol) of product.

The product was then dissolved in 20 ml acetonitrile, filtered using a millipore filter, acidified with 0.25 ml of 5.5N anhydrous HCl in diethyl ether and concentrated to dryness in vacuo affording 0.43g (26%) of a solid foam. 1H NMR(DMSO-dό) δ = 1.74 (m,2H,CH₂); 2.74 (s,3H,NCH₃); 2.88 (t,2H,CH₂); 3.17 (m,7H,SO₂CH₃ + CH₂x2); 3.59-3.74 (m,14H,OCH₃x4 + CH₂NS0₂); 6.63 (d,lH,Ar); 6.71 (m,2H,Ar); 6.88 (m,3H,AR); 7.35 (d,2H,J=8.7Hz,Ar); 7.55 (d.2H,J=8.7Hz,Ar); 10.28 and 10.48 (2 broad s,2H,exchD₂O,NHSO₂ and NH⁺)ppm.

Example 2

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimet oxyphenyl)ethyl]methylamino] propyl] -4-(methylsulphonylamino)benzamide hydrochloride.

A solution of 0.91 g (2.3 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl) ethyl]-N-methyl-l,3-propanediamine and 0.27 g (2.7 mmol) of triethylamine in 20 ml dry chloroform was added dropwise to an ice cooled stirred suspension of 6.31 mg (2.7 mmol) 4-methylsulphonyl amino benzoyl chloride in 20 ml dry chloroform. The reaction mixture was stirred for 18 hours at room temperature then washed with water dried over MgSO4 and concentrated in vacuo to dryness. The residue was purified by chromatography on silica gel using 9:1 methylene chloride: methanol to afford 0.85 g of a compound which was salified in ethanol by addition of 5.5N anhydrous HCl in diethyl ether. The methanolic mixture was concentrated in vacuo to dryness and the residue triturated in diethyl ether to afford 0.82 g (57.3%) of a beige solid. mp around 130°C. ^lH NMR(DMSO-d₆) δ = 1.82-2.05 (m,2H,CH₂); 2.78 (d,3H,J=4.4Hz,CH₃); 2.85-3.05 (m,2H,CH₂); 2.98 (s,3H,CH₃SO2);3.05-3.35(m,4H,CH₂x2); 3.66, 3.68, 3.72 and 3.75 (4s,12H,4CH₃O); 3.82-4.00 (m,2H,CH₂); 6.60-6.95 (m,6H,Ar); 7.00 (d,2H,J=8.4Hz,Ar); 7.26 (d,2H,J=8.4Hz,Ar); 9.99 (s,lH,exchD₂O,NHSO₂); 10.43 (s,lH,exchD₂O,NH⁺) ppm. Example 3

N-(3,4-Dimethoxyphenyl)-N-P-[[2-(3,4-dimethoxyphenyI)ethyl]- methylamino]propyI]-4-(lH-imidazol-l-yI)benzamide- dihydrochloride

Starting from 0.98 g (2.5 mmol) of N-(3,4-dimethoxyphenyl)-N'-[2-(3,4- dimethoxyphenyl) ethyl] -N'-methyl- 1 ,3-propanediamine and 0.54 g (2.6 mmol) of 4- (lH-imidazol-l-yl)benzoyl chloride and following the method described in example 2, yielded 0.56 g (35.5%) of the title compound as beige solid (the compound was purified as described in Example 2). H NMR(DMSO-d₆) δ = 1.86-2.00 (m,2H,CH₂); 2.78 (d,3H,J=3.5Hz,CH₃-NH); 2.92- 3.02 (m,2H.CH2); 3.05-3.50 (m,4H,2CH ); 3.66, 3.68, 3.72 and 3.75 (4s,12H,4CH3θ); 3.84-3.99 (m,2H,CH₂); 6.68-7.08 (m,6H,Ar); 7.56 (d.2H,J=8.2Hz,Ar); 7.71 (d,2H,J=8.2Hz,Ar); 7.89 (s,lH,Ar); 8.29 (s,lH,Ar); 9.73 (s,lH,Ar); 1.83 (s,lH,exchD₂O,NH⁺) ppm

Example 4

4-Acetylamino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)et yl] methylamino] propyljbenzamide, hydrochloride.

110 μl (1.5 mmol) of acetyl chloride were added dropwise to an ice cooled stirred solution of 0.70 g ( 1.38 mmol) of 4-amino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyl) ethyl]methylamino]propyl]benzamide dihydrochloride (description 1) and 0.42 ml (3 mmol) triethylamine in 20 ml methylene chloride. The mixture was stirred for 2 hours then two drops of acetyl chloride were added again and the mixture was stirred at room temperature overnight. The mixture was washed twice with water, dried over MgSO4 and concentrated to dryness. The residue was purified by chromatography on silica gel using 9: 1 methylene chloride:methanol affording 0.55 g of a compound which was taken up in methylene chloride, dried over MgSO4 and concentrated in vacuo to dryness. The residue was salified in methanol by addition of 5.5N anhydrous hydrochloric acid in diethyl ether affording 0.575 g (71%) of the tiltle compound as a foam, mp around 125°C. *H NMR(DMSO-d₆) δ = 1.84-2.05 (m,2H,CH₂); 2.00 (s,3H,CH₃CO); 2.78

(d,3H,CH₃NH); 2.84-2.99 (m,2H,CH₂); 3.04-3.40 (m,4H,CH₂x2); 3.65, 3.68, 3.72 and 3.75 (4s,12H,4CH₃O); 3.82-3.94 (m,2H,CH₂); 6.58-6.94 (m,6H,Ar); 7.22 (d,2H,J=8.6Hz,Ar); 7.42 (d,2H,J=8.6Hz,Ar); 10.08 (s,lH,exch.D₂O,NHCO); 10.15 (s,lH,exch.D₂O,NH⁺) ppm

Example 5

N-(3,4-Dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methyl- amino]propyl]-N'-[4-(methylsulphonyIamino)]urea, hydrochloride.

a/ Starting from 0.4 g (0.7 mmol) of N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyl) ethyl]methylamino]propyl]-N-(4-nitrophenyl)urea (D 2) and following the method described in description 1, afforded 0.27 g (71%) of N-(3,4- dimethoxyphenyl) -N-[3-[[2-(3,4-dimethoxyphenyl) ethyl]methylamino]propyl]-N-(4- aminophenyl)urea. The *H NMR being consistent with the assigned structure this compound was used in the next step without purification, b) To a solution of 0.27 g (0.5 mmol) of the above amine and 0.08 g of triethylamine in 20 ml of methylene chloride, a solution of 0.08 g of methanesulphonyl chloride in 2 ml of methylene chloride were added over a period of 5 min. under stirring. Stirring was maintained for 4 hours at room temperature, and the mixture was concentrated in vacuo. The resulting crude product was dissolved in ethylacetate and washed with water. The organic layer was dried over M SO4 and concentrated in vacuo to dryness.

The residue was purified by chromatography on silica gel using 90:10 methylene chloride: methanol.

The pure compound was dissolved in 90:10 ethylacetate:methylene chloride and salified using one equivalent of 5.5N anhydrous HCl in diethyl ether affording 0.12 g (38%) of the title compound as an off yellow solid, m.p = around 125°C. ^lR NMR (DMSO-d₆) δ = 1.83-1.98(m,2H.CH ); 2.78(broad s,3H,CH₃-NH+); 2.82- 3.03(s,3H,CH₃SO₂ and m,2HCH₂); 3.05-3.4(m,4H,2CH₂); 3.72-3.79(4s,12H,4OCH₃, and m,2H,CH ); 6.70-7.10(m,8H,Ar); 7.35-7.40(d,2H,Ar); 7.67(s,lH,exch.D₂O,NH); 9.44(s,lH,exch.D₂O,NH); 10.1 (broad s,lH,exch D₂O,NH+)ppm

Example 6

N-(3,4-Dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl)ethyl]methyl- amino]propyI]-4-methylsulphonylamino)benzeneacetamide, hydrochloride

a/ Starting from 1.1 g (2 mmol) of N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4- dimethoxyphenyl)ethyl]methylamino]propyl]-4-nitrobenzeneacetamide and following the method described in description 1 afforded 0.4 g (38%) of N-(3,4-dimethoxyphenyl)-N-

[3-[[2-(3,4-dimethoxyphenylethyl]methylamino]propyl]-4-aminobenzeneacetamide.

-1H NMR (DMSO-d₆) δ = 1.43-1.75(m,2H,CH₂); 2.21(s,3H,CH₃N); 2.30-

2.65(m,6H,3CH₂); 3.16(s,2H,CH₂CON); 3.48-3.83(m,14H,4CH₃O and CH₂NCO); 4.88(broad s,2H,exch. D₂O,NH₂); 6.35-7.02(m,10H,Ar)ppm. b) Starting from 0.4 g of the above crude amino and following the procedure b described in example 5 yielded 0;18 g (36%) of the title compound as an orange solid. m.p = around 95°C

1H NMR (DMSO-d₆) δ = 1.70-2.02(m,2H,CH₂); 2.77(d,3H,J=4.2Hz,CH₃NH⁺); 2.82- 3.00(m,2H,CH₂ and s,3H,CH₃SO₂); 3.05-3.30(m,4H,2CH₂); 3.36(s,2H,CH₂CO); 3.55-

3.9(m,14H,4CH₃O and CH₂); 6.63-7.2(m,10H,Ar); 9.66(s,lH,exch. D₂O,NHSO₂);

10.23(broad s,lH,exch. D₂O,NH+)ppm Pharmacological data

Methodology

Guinea pigs (300-350 g) were anesthetized by intravenous injection of sodium pentobarbital (60 mg/kg). After thoracotomy the heart was rapidly excised and placed in oxygenated Tyrode solution. Papillary muscles were removed from the right ventricle. Preparations were then fixed to the silastic base of a 5 ml organ bath and superfused with oxygenated Tyrode solution maintained at 37 ± 1°C. The modified Tyrode solution (pH 7.35) contained the following (mM) : NaCl 125, KC1 4.0, MgCl₂ 0.5, CaCl2 1.8, NaHCO3 24, NaH₂PO40.9 and glucose 5.5. The solution was equilibrated with a gas mixture of 95% O2 - 5% CO2.

After a stabilisation period (at least 1 h), transmembrane action potentials were recorded with conventional microelectrodes (10 MOh ) connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered 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 threshold. The basic cycle length was 1000 ms (PULSAR 6i stimulator). The signals were monitored on a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis. Measurements were made on resting membrane potential (RMP), action potential amplitude (APA) and action potential durations at 30, 50, and 90% repolarization (APD30, APD50 and APD90 respectively). Recordings were made after 30 min of equilibration for each concentration. Only recordings in which the same impalement was maintained throughout the entire experiment were used for analysis.

Claims

1. A compound of formula (I):

B-Ar

(I)

or a salt thereof, or a solvate thereof, wherein

A and B each independently represents a C\._ n-alkylene group wherein each carbon is optionally substituted by a C\- alkyl group;

D represents CO, SO , NH-CO or CH CO;

T represents hydrogen, alkyl, alkenyl or cycloalkyl;

Z represents a bond, CH2, (CH2)2 or X-CH2-CH2 wherein X represents O or S;

R\, R2 and R3 each independently represent H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of R\, R2 and R3 together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen;

R4 represents alkylsulphonamido, alkylamido or imidazo; and

Ar represents substituted or unsubstituted aryl, wherein the optional substituents are the above defined R 1 , R2 and R3

2. A compound according to claim 1, when A represents (CH2)3.

3. A compound according to claim 1 or claim 2, wherein B represents CH2CH2 -

4. A compound according to any one of claims 1 to 3, wherein D represents CO, SO2 or NH-CO or CH₂CO.

5. A compound according to any one of claims 1 to 3 wherein D represents CO.

6. A compound according to any one of claims 1 to 5, wherein T represents CH3.

7. A compound according to any one of claims 1 to 6, wherein R4 is methylsulphonamido, acetamido or a 1 -imidazo group attached at the 4- position.

8. A compound according to claim 1 being:

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl]ethyl] methylaminojpropyl]- 4-(methylsulphonylamino)-benzenesulphonamide;

N-(3 ,4-dimethoxyphenyl)-N-[3- [ [2-(3 ,4-dimethoxyphenyl)ethyl] methylamino] propyl] - 4-(methylsulphonylamino)benzamide;

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]- methylamino] propyl] - 4-(lH-imidazol-l-yl)benzamide;

4-acetylamino-N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino] propyl] benzamide;

N-(3,4-dimethoxyphenyl)-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methyl-amino]propyl]- N'-[4-(methylsulphonylamino)]urea; and

N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl)ethyl]methyl-amino]propyl]-4- methylsulphonylamino)benzeneacetamide; or a salt thereof, or a solvate thereof.

9. A process for the preparation of a compound of formula (I), which process comprises reacting a compound of formula (II):

(II)

wherein A, B, T, Z, R\, R2, R3 and Ar are as defined in relation to formula (I) with a compound of formula (III);

, ^X

(HI) wherein R5 is R4 as defined in relation to formula (I) or a group convertible into R4, providing that: (a) for the preparation of compounds of formula (I) wherein D is CO, CH2CO or SO2, X represents CO.Li, CH2CO.L1 or SO2L1 respectively, wherein _,\ is a leaving group or atom, such as a halogen atom; or

(b) for the preparation of compounds of formula (I) wherein D is NH.CO, X is N=C=O; and thereafter, if required, carrying out one or more of the following optional steps:

(i) for compounds wherein R5 is not R4, converting R5 into R4;

(ii) converting a compound of formula (I) into a further compound of formula (I);

(ii) preparing a salt of the compound of formula (I) and/or a solvate thereof.

10. A pharmaceutical composition comprising a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.

11. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

12. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of arrhythmia and ischeamic rhythm disorders.

13. 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 and ischeamic rhythm disorders.

14. A method for the treatment and/or prophylaxis of arrhythmia and ischeamic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of 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.

15. An intermediate, being a compound of formula (II):

(II) wherein A, B, T, Z, Rj, R2, R3 and Ar are as defined in relation to formula (I) of claim 1.