AP694A

AP694A - Nitro-benzamides useful as anti-arrhythmic agents.

Info

Publication number: AP694A
Application number: APAP/P/1997/000965A
Authority: AP
Inventors: Guy Marguerite Marie Gerard Nadler; Michael Jean Roger Martin
Original assignee: Smithkline Beecham Laboratoires Pharmaceutiques
Priority date: 1994-10-26
Filing date: 1995-10-24
Publication date: 1998-11-18
Also published as: CZ125297A3; EP0788474B1; DE69516708T2; TR199501320A2; ID18094A; JPH10508013A; US20020107243A1; EP0788474A1; AU697357B2; MA23706A1; UA50722C2; PL319904A1; PT788474E; KR100369958B1; FI971755A7; US20010025054A1; FR2726267A1; CA2203814A1; MX9703112A; FI971755A0

Abstract

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 attached to adjacent carbon atoms any two substituents 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; A represents a Cj-4n-alkylene group wherein each carbon is optionally substituted by 1 or 2 Ci-6alkyl groups Ri represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of R2, R3 and R4 represents nitro the remaining member of the group of R2, R3 and R4 represent hydrogen; X represents a -CO-NH- moiety; and Z represents Cj-tf-alkylene groiv . 1 carbon is optionally substituted 1 or 2 Ci-6altyi groups; a process for preparing such compounds, pharmaceutical compositions comprisinj such compounds and the use of such compounds in medicine.

Description

NITRO-BENZAMIDES USEFUL AS AKTI-ARRHYTWIC AGENTS

The invention relates to certain novel compounds, to pharmaceutical compositions containing such compounds, to a process for the preparation of such compounds and to the use of such compounds as active therapeutic agents.

Anti- arrhythmic agents ? classified according to their electrophysiological effects en the cardiac cell (Vaugham-WilliaiBii, 1970,1989): ciuss I agents blux the fast sodium current, class Π agents are beta-adrenergic blockers, class ΠΙ agents block potassium cuiVeuts, chu·., ..7 agents block the calcium current, and class V agents are rcdf 7 ί/',ϊ Λ,ο.,ν ztdtihkwis.

A majority of ventricular and atrial arrhythmias are related to reentrant circuit. The. prolongation of myocardial refractoriness within or surrounding such a reentrant circuit is a potential mechanism for the management of cardiac arrhythmias.

Because class HI antiarrhythmic agents block cardiac potassium currents, they 15 prolong the repolarisation process and increase refractoriness. Consequently class ill agents represent the most specific class to treat reentrant arrhythmias.

However, due to their mechanism of action, te. a concentration dependent increase in t’ rrdiac action potentia’ “'^ration, higher doses of class HI antiarrhytiimic agents may trigger arrhythmias. Such arrhythmias, called Torsade de

Pointe represent the main adverse effect for all pure class ΙΠ compounds currently in .> European Patent Application, Publication Number 0 245 997 dis closes certain aminoethylsulphoanilides which are stated to have pure class ΣΠ antiarrhythmic properties.

It has now been discovered that certain novel substituted 4-nitrobenzantide derivatives induce a self-limiting increase of the cardiac action potential duration, related ro a dual blockade of cardiac potassium and calcium channels. Consequently, they are considered to be useful anti-arrhythmic agents having an improved pharmacologic ;1 p ifUe over pure class HI anti-anhythmic agents, in particular they are considered to show a low proarrhythmic potential and readily restore the contractile function of the ischaemic myocardium. They are considered to be particularly useful for the treatment of atrial or ventricular cardiac arrhythmias.

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

,P/P/ 7/(0953

- 1 or a salt thereof, or a solvate thereof, wherein

Ar represents substituted or unsubstituted aryl, wherem the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms any two substituents together vith 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;

A represents a Cj_4 n-alkylene group wherein each c ixfcon is optionally substituted by 1 or 2 alkyl group?;

Rj represents hydrogen, alkyl, alkenyl or cycloalkyl;

one or two of the group of R_2> ^4 represents nitro As remaining members of

Ae group of R2, Rj and R4 represent hydrogen;

X represents a -CO-NH- moiety; and represents C2-4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C 1.5 .Ikyl groups.

Suitable substituents for Ar are 1, or favourably, 2 alkoxy groups, especially meAoxy groups, the substituents favourably being attached at Ae 3- and 4- positions relative to Ae point of attachment cf Ar to variable A.

Preferably, Ar represents 3,4«b .-.rmoxyphenyl

Suitably, A represents an unsubstituted C1.4 n-alkylene group.

Preferably, A represents -CHj-CHj.

When Ri is alkyl ii b preferably b'M web as CR rifcyfe r₃ Ripfe Q dkyl,

C5 alkyl or Q, alkyL

In one aspect, Ri is alkylene or cycloalkyl.

Preferably, R| is hydrogen.

Suitably, any one of R2, Rj and R4 represents niuo and Ae remaining members of Ae group of R2, R3 and R4 represent hydrogen.

Preferably, R2 repn ents 4-nitro.

Preferably, Rj and R4 each represents hydrogen.

Suitably, Z represents an unsubstituted C2-4 n-alkylcne group.

Suitably, Z represents CH2CH2CH2.

A particularly preferred compound of formula is N-[3-[[2-(3,4diraeAoxyphenyl)eAyl]amino]propyl]-4-nitro benzamide or a salt Aereof, such as a hydrochloride salt, or a solvate thereof.

As used herein unless oAerewise stated, Lie 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 part of oAer groups such as alkoxy or arylalkyl groups.

As used herein, Ae term alkylene includes straight or branched chain alkylene groups having from 2 to 12, favourably 2 to 6 carbon atoms.

-2AP. Ο Ο 6 9 4

As used herein, the term cycloalkyl includes C3-« cycloalkyl groups, favourably C5-6 carbon groups.

As used herein, unless otherwise stated, Lhe term aryl includes phenyl and naphthyl, preferably phenyl.

As used herein, unless otherwise stated., halogen includes fluorine, chlorine o^r offiine.

As used hexcin, the term cardiac arrhythmia relates to any variation from the normal m nf heart beat, including, ' rithc t limitatic:;, sinus arrhythmia, premature heartbeat, heariblock fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.

The compounds of formula (I) 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 extends to any of the stereoisomeric forms, including enantiomers of the compounds of formula (I) end 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 -^specific cr asymm- ?..dc svr'-'*sses.

'....•ae ph·, .naaccudcallj·,. xcptable of the compounds of formula Q) inclu.ri. acid addition salts with pharmaceutically acceptable mineral acids such as hydrochloric, hydrobremic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic : . ns ?ceric, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto-glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids. Preferably the acid addition salt is a hydrochloride.

Pharmaceutically acceptable sails Pi ,rede pharmaceutically acceptable N25 oxides, and the invention extends to these.

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

The salts anti or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of phaxmceutically 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 (T), or a salt thereof, or a solvate thereof, may be prepared by reacting a compound of formula (Π):

I¹

H₂N~~- Z-~ N~A —“Ar

8 6 0 0 /46 /d/dV

-3AP.00694 wherein A, Ar, R j and Z are as defined in relation to formula (I), with a compound of formula (ΙΠ):

CO-L, (HI) wherein Rj, R-? aH R4 am ss defined ia relation to foranda (I) sad Lj represents ?. leaving group; and thereafter, if required, carrying out one or mere of the following optional steps:

(i) 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 phannaceuticahy acceptable solvate thereof.

Compounds of formula (HI) are known, commercially available compounds. The reaction between the compounds of formulae (Π) and (ΙΠ) may 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 which provides a suitable rate of formation of ϋαα required product, generally at a low to ambient temperature, preferably ambient.

A preferred leaving group I4 is a halogen atom, such as a chlorine atom.

The compounds of formula (Π) «re known compounds and may be prepared by the method described in Offenlegungsschrift 2345423.

The compounds of formula (H) may also be prepared by reducing a compound of formula (TV):

S9660/Z6 /d/d¥

R,

Η,Ν—CO- 2— N-A — Af (IV) wherein A, Ar and Rj are as defined in relation to the compound of formula (I) and Zj represents £4..3 n-alkylene group wherein each carbon is options'!;/ substituted by a Ci_g alkyl group.

The reduction of the compounds of formulae (IV) may be carried out using conventional reducing agents and conditions, for example by using a metal hydride reducing agent, sue'. as lithium aluminium hydride, in an aprotic solvent, such as tenahydrofuran or diethyl ether or mixtures thereof, at a temperature which provides a suitable rate of formation of die required producti generally at an elevated temperature and conveniently at the reflux temperature of the solvent

The compounds of formula (TV) may be prepared by reacting a compound of formula (V):

-4AP.00694

Τ’

Η Ν“Α — Ar (V) wherein A, Ar and Rj are as defined in relation to the compound of formula (I), with a 5 compound of ^ormuls (Yl)' (Va) wherein Zj is as defined in relation to the compound of formula (TV) and L2 represents a leaving group.

The reaction between the compounds of formulae (V) and (VI) is carried out in an aprotic solvent, s . *h as acetonitrile, at a temperature whi- h provides a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent; preferably the reaction is carried • out in tii© presence of base, usually an orgaric ba:/·: such as a trialkyh'; ^;ne, fr · examp⁵ ·. triethyfitmme era comple:: such as _k fi //fifi. extiu

Ando, Junto Yamawaki, Chemistry Letters, 1979, p.45).

A preferred leaving group L2 is a halogen atom, such as a chlorine atom.

’ ·-·'I

The compounds of formula (VI) arc known compounds or they arc prepared using methods analogous to those used to prepare known, commercially available compounds.

In a further aspect the invention provides a process for the preparation of a 25 compound of formula (I), which process comprises demethylating a compound of formula (ΥΠ):

AP/P/ 9 /00965

CH, ^R3/^fV__x„_Z_'_A^ (VH) wherein A, Ar, R2» ^3» are as defined in relation to the compounds of formula (I); and thereafter, as required, converting any -NH- moiety so formed into a group NR, wherein R, represents C_w alkyl, an alkenyl or a cycloalkyl group.

Ifie demethylation of the compounds of formula (VH) may be affected by using any conventional demethylation process, for example by use of methods diseas'd fit fi

Org. Chem., t97.fi 40, 1850, ibid, 1984,49,2081 or those me»hods disclosed in Symh&sis 1591,313.

-5AP. 0 0 6 9 4

The conversion of any -NH- moiety into a group NR5 wherein R5 represents a alkyl, an alkenyl or a cycloalkyl group may be carried out using conventional alkylation, alkcnylation or cycloalkylation methods, by use of the appropriate alkylhclide, alkenylhalide or cycloalkylhalide, suitably an iodide, in the presence of a base such as potassium bicarbonaie in an aprotic solvate such as tetrahrydrofuran.

In a further aspect the invention provides a compound of formula (VH) or a salt thereof or a solvate thereof as m intermediate.

A compound of formula (I), or e. salt thereof, or solvate thereof, may also be prepared by reacting a compound of formula (ΥΠΙ):

wherein R2, R3 R4 X and Z arc as defined in relation ;·> ή : ;vv ( ) and L3 is a leaving group, such as a halogen, with a compound of formula (DC):

Ph

HN-A ·—A* 0-Λ wherein A, Ar, A j ere as defined A . · n ί' formula ©; sad the. . ·, carrying out one or more of the following optional steps:

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

The reaction betw cn the compounds of formulae (VIS) and (IX) may t > 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 which provides a suitable rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent

A suitable value for Lj is chlorine.

A compound of formula (VSI) may be prepared by reaction between a compound of above defined formula (01) and a compound of formula (X):

H2N-Z-L3 (X) wherein Z is as defined in relation to formula (I) and L3 is as defined in realtion to formula (VIE).

The reaction between the compounds of formulae (HE) and (X) may be carried under conventional acylation conditions for example in an Lui solvent, such as

-6AP/P/ 97/00565

AP.00694 dichloromethane, in the presence of a base, usually an organic base, for example v iethylamine, at a temperature which provides a suitable rate of formation of the required product, generally at a low to ambient temperature, preferably at ambient temperature.

The compounds of formula (X) are known, commercially available οοπιτχηιη-Τ, / suitable conversion of one compound ot formula (X) into a further compound of fotmtda (I) involves the interconversion of variable Rt m the compounds of formula (1), for x-rmiple the conversation of co.··::; vterdA D.j h Ί k::o compc?· *ds of formula (I) wherein Rj represents alkyl, suitably Cm alkyl, alkenyl or cycloalkyl or the above mentioned conversation of compounds wherein Rt is methyl into compounds wherein Ri is hydrogen, Cm alkyl, alkenyl or cycloalkyL

It will be appreciated that in any of the abovementioned reactions and conversions any reactive group in the substrate molecule may be protected, according to conventional chemical practi · The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.

As mentioned abov; the ccmsounds of the invention are indicated as having useful tiier₆r •-.udeproj'.'. ties: The ?,.'Psent inve··,· ‘urdingiy provides a comp?vnd of formula (ί), or ' > > itcaily accepti?¹” ‘ and/o’'«ph--a'mac./'ti.e^,?k' acceptable solvate &· „u.uf, for usa as an ac ’* i ifictapeutic subst?

More particularly, the pre ·-' n proviht ,» . _ ... T(J), (./:

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 <© σ>

C Λk-'.

arrhythmia such as ventricular arrhythmia, also ischaemic rhythm disorders.

/d/dv

A ompound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pL maceutically acceptable solvate thereof, may te administered ρ,’Γ ££ or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable cams·.

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 pharmaceutic .Oy acceptable carrier therefor.

A compound of formula (I) or a pharmaceutically acoekable salt ‘ hereof and/or a pharmaceutically acceptable solvate thereof is normally administered in unit dosage fOlUL

An amount effective to treat the disorder hereinbefore described depends upon such factors as the efficacy of a compound of farrorl? (I), the y articular 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.

-735

UV

AP. Ο Ο β 9 4

However, a unit dose will normally contain 0.1 to 500 mg for example 2 to 50 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 rimes a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more usually 1 to 1000 mg, for example 1 to 200 mg, that is in the range of approximately 0.02 to 3 mg/kg/day, more usually 0.1 to 3 mg/kg/day, for example 0.15 to 2 mg/kg/day.

At the above described dosage range, no toricobgicrf effects are indicated for !Ο the compounds of the invention.

Jn such treatment, the compound iazy 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 bs in die form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable sd^;'¹ ’ ^;ons or suspensions, suppositories and transdennal devices. Orally administrabie 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 io 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 die 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 prepar tions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be pt ..seated 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, ιλ c„o £

&

<

carboxymcihyl 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-hydroxybenzoatc or sorbic acid, and if desired conv-redond flavouring or colouring agents.

Fo. parental administration, fluid unit dose forms are prepared containing a compound o ^<4-e present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be eititer suspended or dissolved. Parenteral 10 solutions are normally prepared by dissolving the active compound in a vehicle ; d 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 ia 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 preps., 1 in substantially the same manner except that the active c ampound is suspended in the vehicle instead of being dissolved and sterihsed by exposure to ethylene oxide before suspending in sterile vehicle. Advantageously, a surfactant or wetting agent is included in die composition to facilitate uniform distribution of the active compound.

iw i,._t 7 . nninistrarioii, the composition muy bn in the fora ' 'dermal ointment orpn>^-f,h for systemic delivery of the compo-red«odf.'.-4ayh. ... . . ? n conventional manner, for example, as described in the standard textbooks such as Dennatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical Sciences Dekker) cr Hatrys Cosmeticology (Leonard Hill Book*).

In addition rach compositions may contain further active agents sucu as anti-hypertensive agents arid diuretics.

As is common practice, the compositions will usually bs accompanied by written or printed directions for use in the medical treatment concerned.

As used herein the term 'pharmr, sutically acceptable' embraces compounds, compositions and ingredi nts 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 ventrical nr arrhythmia, and also ischemic rhythm disorders in a human or non-human mammal which comprises administering an effective, non-tox c, 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 mamxnal in need ’hereof.

79//00965

-9AP.00694

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 ischaemic arrhythmia 5 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 i-re 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 ischaemic rhythm disorders.

No toxicological effects arc indicated when a compound of formula (I) ot a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvai thereof is administered in the above mentioned dosage ranges.

Th;s following Description and Examples illustrate the invention bat do not linait it in any way.

-10AP.00694

Description 1

3-[[2-(3,4-Dimeihoxyphenyl)ethyi]methylamino] propanamide ch₃

OCH

OCHj

DI

6.42g (6ommol) 3-Chloropropa.namide, 5.85g (30mmol) N-methy 1-3,4dimcthoxybenzeneethanaraine and 7.7g (75mmol) triethylamine in 100ml acetorntriie were stirred under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silicagel using methylene chloride/methanol: 92/8 to y ield 5.12g (64.1%) of the desired compound as an orange oiL

Ή NMR (CDC1₃) δ = 2.40 (s,3H,NCH₃); 2.46 (q2H,J=5.9Hz,CH2); 2.74-2.79 (m,6H,3CH2); 3.85 and 3.87 (2s,6H^CH₃O) ; 6.70-6.78 (m,3H,3Ar); 7.71 (broad bancL2H,exch DpO ,ΝΗ-^) ppm.

Description 2 js{.[2-(3_t4-diniethoxyphenyl)cthyl]-N-methyl-l,3-propanedianune

dry tetrahydrofuran were added dropwise to a suspension of 0.64g (1.7 mmol) lithium aluminium hydride in 20ml dry diethylether whilst stirring. The mixture was heated under reflux for 2 hours then co·.··' with a bath of Le water before carefully adding 25 dropwise 0.65ml water, 0.65ml U% aqueous NsQH, then 1.95ml water. The mixture was dried over MgSC/4, concentrated vi va.ruo and the residue was purified twice by chromatography on basic alumina using methylene chloride/methanol: 95/5 then methylene chlorideAnethanoV30% aqueous ammonia: 90/10/0.1 to yield 0.86g (60.8%) of the desired compound.

AP/P 8 7 · ' .965

Ή NMR (CDC1₃) δ = 1.65 (00,211/¾) ί ²·¹⁵ (hroad band^H,exch D₂OJ4H2) ; 2.30 (s,3H,NC%); 2.47 (qHiJ ; 2.53-2.79 (m,611,301¾); 3.85 and 3.87 (2s,6H4CH₃O); 6.71-6.82 (m,3H,3Ar) ppm.

- 11 AP.00694

Description 3

N-(3-Qiloropropyl)-4-nitrobenzaniide

A solution of 6.43g (49mmol) 3-chloropropylamine and 13.6ml (98mmol) triethylamine in 220ml methylene chloride was cooled by an ice bath and 9g (48.5mmol) 4-mtrobenzoyl chloride were added fractionwise. After one hour stirring at room temperature the organic phase was washed twice with water, dried over MgSCh and concentrated in vacuo to afford 10.68g (91 %> of beige crystals. ^lH NMR was consistent with the desired structure.

Example 1

N-[3-[[2-(3,4-Dimethoxyphenyl)cthyl]methylamino]propyI]-4-nitTObenzamide 15 hydrochloride

800mg (3.17m ·?!) N-[2-(3_s4-Dirosthr'.·: _· /., ,_u . ’-I,· , . , (F /630mg(3.33ramol) ’ιΛοbe* Yrtf C/Sp(b/dr „ in bOml methylene chloride were stirred for 2 hours at room temperature. Tae mixture was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified twice by chromatography on silicagel using methylene chloride/methanol: 97/3 then 94/6 yielding 70Qmg (55%) of the desired compound as a base. The compound was salifi· «1 in methylene chloride by adding a solution of hydrcehorie acid in diethyl ether yielding 594mg (43%) of the desired compound as a yellow solid: mp = 80-90°C.

NMR (DMSO-d^) δ = 2.00 (m,2H,CH2) ί 2.79 (s,3H,NCH₃); 2.90 (m,2K,CH₂); 2.95 (kl2H,CH2) ; 3.20 (m,211,0¾); 3.35 (πι^Η,Οφ; 3.72 and 3.74 (2s,6H^CH₃O); 6.80-6.96 (m,3H,Ar); 8.12 (d,2HJ=7.9HzAr); 8.33 (d,2HJ=7.9Hz,Ar); 9.05 (broad band,lH,exch D₃O,NH); 10.45 (broad band,lH,erch D₃O JNH) ppm.

Example 2

N-[3-[[2-( ;,4-Dimethoxyphenyl)ethylJamino]propyI]-4-ni£ro benzamide hydrochloride

AP/F; 7 0 2 6 5

- 12A solution of 10.62g (44mmol) N-(3-chloropropyI)-4-nitrobenzamide (D3), 8.1g (45mmol) homovcratrylamine and 6.26ml triethylamine in 200ml methylene chloride was refluxed for 48h. The solvent was then concentrated in vacuo and the residue dissolved in water. The aqueous phase was first washed vrith methylene chloride, then made basic with aqueous NaOH and finally extracted twice with methylene chloride. This second organic phase was dried over MgSO₄ and concentrated in vacuo affording 12g of a crude residue. This residue cd by chnomatognphy on sIHeag-si uah.

CEiQa/MevRiriluOH : 85/10/5 ra axiud 4.^g of the tide compound as an yellow oil (free base),

This compc-und was dissolved in methanol and acidified ' solution of ar\ hydrogen chloride in diethyl ether, affording after drying 4.4g of the tide compound as light beige crystals, mp.: 141-2°C *H NMR (DMSO-d6) δ = 1.93 (m, 2H, CH₂); 2.89-3.16 (ra, 6H, 3xCH₂); 3.40 (m, ?H, CHz); 3.72 and 3.75 (2s, 6H, 2xOCH₃); 6.74-6.91 (rn, 3H, Ar); 8.12 (d, 2H, J =

8.6Hz, Ar); 8.32 (d, 2H, J = 8.6Hz, Ar); 9.12 (broad band, 2H, exch. DaO, NH₂+);

9.15 (t, IH, exch. E^O, NH) ppm.

Pharmacologies! data Methodology

Guinea pigs (300-350 g) were anesthetized by intravenous i)ri ;,tion of sodium pentobarbital (60 mg/kg). After th^racof.;>my the heart was rapidly excise;, -wid placed in oxygenate · Tyrode solution. PapR; nuscles were rem-ty.’'·;·* Com thn right ventricle. ! <.<.'> ^rations ” t '4 on fixed . ·; silastic hva* j. v · ·;β orga bath and supa'fused ?/ ri oxygenated Tyrode :·· ' Ron maintained at 37 ±1®C

The yBxri·' ' ' '’cb-A svbtfr·..... pHoatsinsd ihe fellowb? (mM): NaCl IR,

KCi 4ri --2 03, C«Rri_ 4., R W3 24. NaKjPQ^ 03 · 1 glucose 5.5. The solution was equilibrated with a gas Rxmre of 95% O2 - 5% CO2·

After a stabilisation peric 1 (at least lh), transm.,2/ _: ns action potent!..4. /ere recorded with conventional tnicroelecurodes (10 Milan} connected to a high input impedance amplifier (BIOLOGIC VF 180). External stimuli were delivered to the preparation with bipolar platinum electrodes placed εϊ one end of the muscle. The pulse duration was 1 ms and the amplitude was twice threshold. The basic cycle length was 1000 uis (PULSAR 6i stimulator). The signals were monitored oa a storage oscilloscope (GOULD 1602) and simultaneously recorded on a digital tape recorder (BIOLOGIC DTR 1200) for further analysis.

Measurements were made of action potential amplitude (APA) and action potential durations at 30 and 90% repolarization (APD30 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 usee for analysis.

‘ώ>

- 13?·& o,_s.

AP . 0 0 6 9 4

Increase in APD (%)

0.3 1 3 10

Drug concentration (μΜ)

Effect of compound of example 1 on action potential duration (APD) recorded in guinea-pig papillary muscle. Action potential duration was measured at 30% (APD3C) and 90% (APD90) of repolarization.

CA

O o

r*·^ <A a

ί <

- 14A 'P . 0 0 6 9 4

uc-rantM d<sratha unease % change from Control

Affect of c: ’’nple 2 on ac<k ·<)% of lepoiarizaac? (AD J30) id at 90% of repolarization (APD90) in guinea-pig isolated papiilaiy muscle. Values are mca changes in percent from the control value measured in the absence of compound (0).

Claims

Cly inis

1. A compound of formula (I):

R.

R.

X— Z— N-A —Ar

R.

(I) or a salt thereof, or a solvate thereof, characterised in that:

Arrepresents a phenyl group substituted with 1 or 2 alkoxy groups;

A represents a C4.4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C].g alkyl groups;

R] represents hydrogen, alkyl, alkenyl or cycloalkyl;

one or two of the group of Ro, R3 and R4 represents nitro the remaining members cf tire group of Ro, R3 and R4 represent hydrogen;

X represents a -COtitiK- moiety; and
2 r ^presents Cg„4 n-alkylene group wherein each carbon is optionally substituted by 1 or 2 Cj.g alkyl groups.

2. A compound according to any one of claim 1, wherein R, represents hyt.rogen, C₂.₆ alkyl, alkenyl cr cycloalkyl.
3. A compound according to claim 1 or 2, wherein R_t is hydrogen.
4. A compound according to any one of claims 1 to 3, wherein one of Rp, R3 and R4 represents nitro and the remaining members of the group of R2, P.3 and R4 represent hydrogen,
5. A compound according to claim 4, wherei n Rg represents 4-nitro and R3 and R4 each represents hydrogen.
6. A compound according to any one of claims 1 to 5, wherein Z represents CH₂CH₂CH2.

-167. A compound according to claim 1 being N-[3-[[2-(3,4dime’hoxyphenyl)ethyl]amino]propyl]-4-nitro benzamide; or a salt thereof, or a solvafc thereof.

5 8. A process for preparing a compound of formula (I) as defined in claim 1, or a yah 'hereof, or a solvate thereof, which process comprises:

(i) reacting a compound of formula (11):

H.N— 2 —

N-A —Ar (II) wherein A, Ar, R[ and Z are as defined in relation to formula (I), with a compound of formula (III):

R„

R-CO-L,

R, , . ,l.x , C .1·.

L i represents tea ung group; or (h) demethylating a compound of formula (VII u '---X—Z— N-A —Ar (VII;

whciein A, Ar, Ro, R3, R4, X and 2 are as defined in relation to the compounds of formula (I); and thereafter, as required, converting any -NH- moiety so formed into a group NR_S wherein R₅ represents C₇.„ alkyl, an alkenyl or a cycloalkyl group; or (iii) reacting a compound of formula (VIII): 30

-17'' MP .υ ο β

R.

X-Z-L.

(VIII) wherein Rg; fo fo f ^and 2 are as defined in relation to formula (I) and L₃ is a leaving group, such as a halogen, with a compound of formula (IX):

Η N-A —Ar wherein A, Ar, Rj are as defined in relation to formula (I);

and thereafter carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound of formula (ii) preparing a salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

formula (I), as

A. phswmaosutic'd composition comprising a defined in claim. 1, or a phannaceiitically acceptable salt thereof and/or a
10. A compound of formula (1), as defined in claim 1, or a pharmaceutically acc ;ptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
11. A compound of formula (I), as defined in claim 1, or a pharmaceutically acc eptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of arrhythmia.
12. The use of a compound of formula (I), or a pharmaceutically acceptable salfcthcrcof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of arrhythmia and ischaemic rhythm disorders.

-18AP.U Ο 6 y 4
13. A method for die treatment and/or prophylaxis of arrhythmia and ischaemic 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 pham taceutically acceptable solvate thereof to a human or non-human mammal in need thereof.