ANTI-ARRHYTHMIC AGENTS

Abstract: Compounds of the formula: in which Y is -(CH₂) n - where n is one of the integers 1,2,3 or 4 or -CH₂-CH₂-; Z is --SO₂- or -SO₂- where R is hydrogen, alkyl, polyfluorinated alkyl, -CN, cyanoalkyl, cycloalkyl or cycloalkylalkyl; R², R³, R⁴, R⁵, R⁶ and R⁷, independently, are hydrogen, alkoxy, trifluoromethyl or halo; R⁸ is hydrogen or alkyl; R⁹ is alkyl; R¹⁰ is alkyl; m is one of the integers 0 or 1; p is one of the integers 0, 1, 2 or 3; and s is one of the integers 0 or 1; or a pharmaceutically acceptable salt thereof, are useful as anti-arrhythmic agents.

Description: ANTI-ARRHYTHMIC AGENTS The invention relates to novel compounds useful as pharmaceuticals, particularly as anti-arrhythmic agents, and pharmaceutical compositions containing them. Pharmacological agents possessing the ability to block cellular transmembrane influx of calcium are capable of suppressing that portion of myocardial or vascular smooth muscle contractility which is dependent upon extracellular calcium. Church et al., Can. J. Physiol. Pharmacol., 58, 254 (1980); Fleckenstein, Calcium and the Heart, P. Harris and L. Opie, eds., Academic Press (1971); Nayler et al., Bas. Res. Cardiol., 76, 1 (1981); Calcium Blockers, S. Flaim and R. Zelis, eds., Urban and Schwartzenberg, (1982). These pharmacological agents, termed calcium entry blockers, have been proven to be useful in the treatment of hypertension, cardiac arrhythmias, angina pectoris, and coronary artery vasospasm (a possible cause of sudden cardiac death syndrome). Circ. Res., 52, Suppl. I, (1983); Hypertension 5, Suppl. II, (1983). In theory, calcium entry blockers are thought to act by blocking calcium influx through discrete calcium channels (slow channels) in cell membranes. Various tissues exhibit relative differences in sensitivity toward the calcium blocking effect achieved by certain calcium antagonists, theoretically as a result of tissue specific differences in the calcium channels. Acta Pharmacol. Toxicol. 43, 5 (1978); loc. cit. 291 (1978); Microvascular Res., 5, 73 (1973); Am. Rev. Pharmacol. Toxicol., 17, 149 (1977). It is believed that the slow calcium current is responsible for activation of pacemaker cells in the sinoatrial node and the atrioventricular node of the heart. Verapamil, a known calcium channel blocking agent, is believed to slow conduction velocity through the atrioventricular node of the heart, in explanation of the mechanism of its antiarrhythmic activity. In accordance with this invention there is provided a group of new compounds of the formula: EMI2.1 in which Y is -(CH2)n- - where n is 1,2,3 or 4 or EMI2.2 (preferably -(CH2) n where n is 2,3 or 4); EMI2.3 where R is hydrogen, alkyl of 1-6 carbon atoms, polyfluorinated alkyl of 1 to 6 carbon atoms, -CN, cyanoalkyl in which the alkyl moiety contains 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 4 to 8 carbon atoms (preferably alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms); R2, R3, 4 R5, R6 and R7, independently, are hydrogen, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; R8 is hydrogen or alkyl of 1 to 6 carbon atoms (preferably alkyl of 1 to 3 carbon atoms); R9 is alkyl of 1 to 3 carbon atoms; ; R 10 is alkyl of 1 to 3 carbon atoms; m is 0 or 1 (preferably 0); p is 0, 1, 2 or 3 (preferably 1, 2 or 3); and s is 0 or 1 (preferably 0); or a pharmaceutically acceptable salt thereof, with the provisos that the sum of m, p and s must be 1,2,3 or 4; and the number of linear atoms in the bridge connecting the two aromatic rings does not exceed 9; and when Y is methylene or dimethylene, two of R2, R3 and R4 are other than hydrogen. The preferred compounds of the invention from the standpoint of production economics and activity profile may be grouped as those in which (1) the aromatic ring to the left of the depicted structure contains three substituents in the 2-, 3- and 4- positions or the 3-, 4- and 5- positions where, preferably those substituents are lower alkoxy (most preferably methoxy), Y is trimethylene, m and s are 0 and p is 2; (2) the aromatic ring to the left of the depicted structure contains two substituents, either in the 3,5- or 3,4- positions, where preferably those substituents are lower alkoxy (most preferably methoxy) or halo (most preferably -Cl), Y is di, tri- or tetra- methylene, m and s are 0 and p is 2; and (3) the aromatic ring to the left of the depicted structure contains one substituent, in meta position, Y is trimethylene, m and s are 0 and p is 2. As subgeneric aspects of the invention there may be mentioned the compounds having formula I and their pharmaceutically acceptable salts where either (i) the number of linear atoms in the bridge connecting the two aromatic rings does not exceed 8 or (ii) Y is tetramethylene whilst m and s are 0 and p is 2. As preferred subgeneric aspects of the invention there may be mentioned compounds having the formula Ia, Ib, Ic and Id EMI3.1 EMI4.1 in which Z represents EMI4.2 where R is alkyl of 1 to 4 carbon atoms; Rê is hydrogen or alcoxy of 1 to 3 carbon atoms; R3, R4, R6 and R7 are, independently, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; n is 2,3 or 4 and p is 1 or 2; and the pharmaceutically acceptable salts thereof. As aspects of these preferred compounds there may be mentioned the compounds of formulae Ia and Ib (where n is 2 or 3) and of formula Id and their pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the antiarrhythmic agents of this invention are prepared directly by neutralization of the free base or by metathetical displacement. The physiologically acceptable salts may be formed with organic or inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, sulphonic, nitric, methylsulphonic, acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, lactic, naphthalenesulphonic acid, and the like. The new compounds having formula I contain a secondary or tertiary amine function and an N-substituted thioamide function. The compounds may therefore be prepared by various methods available for the preparation of secondary and tertiary amines (alkylation of amines, reductive amination of carbonyl compounds and reduction of Schiff's bases, amides and thioamides) or for the preparation of N-substituted sulphonamides (sulphonylation of amines and alkylation of sulphonamides). In the following description to explain the methods that may be used to prepare the compounds of the invention the following symbols will be used for brevity, namely Ar to represent the group having formula XIX EMI5.1 (where R2 4 are defined supra); R to represent any meaning of R other than hydrogen; R12 represent hydrogen or alkyl of 1 to 5 carbon atoms; AÚ to represent hydrogen or alkyl of 1 to 3 carbon atoms; Aê to represent such a group that AÚAêCH- is the same as the substituted lower alkyl EMI5.2 (where R5, R6, R7, R9, R10 m, p and s are as defined supra); X to represent 0 or S; Y' to represent the same group as Y save that if a hydroxy group is present it may be protected by a removable protecting group and q to represent the integer n-l where n is 2, 3 or 4, i.e. q is 1, 2 or 3. All other symbols such as Z, R 8, and R have the same meaning as in formula I. The invention provides a process for the preparation of a compound having formula I or a pharmaceutically acceptable salt thereof, which comprises (1) sulphonylation of an aromatic amine Ar-NHR to introduce the sulphonyl group having the formula II; -SO2-YÚ-NR8-CHAÚAê (II) or (2) sulphonylation of an amine having the formula III H*NR-YÚ-NR8-CHAÚAê (III) to introduce a sulphonyl group having the formula Ar-SO2- at the nitrogen atom marked with an asterisk; or (3) alkylation of a sulphonamide having the formula Ar-SO2-NHR (IV) to introduce a substituted alkyl group having the formula V; -V1-NR8-CHA1A2 (V) or (4) alkylation of an amine having the formula VI Ar-Z-V1-N*HR8 (VI) to introduce a substituted alkyl group having the formula -CHA 1A2 at the nitrogen atom marked with an asterisk; or (5) reductive amination of a carbonyl compound having the formula A1A2C=o (VII) with an amine having the formula VI as illustrated above; or (6) reduction of a Schiff's base having the formula VIII or IX Ar-Z-V1-N=CA1A2 (VIII) Ar-Z-(CH2)q-C=N-CHAÚAê (IX) or of an amide or thioamide having formula X or XI; Ar-Z-YÚ-NR8-CX-Aê (IX) Ar-Z-(CH2)q-CX-NR8-CHAÚAê (XI) or (7) alkylation of an amine having the formula XII HNR8-CHA1A2 (XII) to introduce a substituted alkyl group having the formula XIII; Ar-z-YÚ- (XIII) or (8) reductive amination of an aldehyde having the formula XIV Ar-Z-(CH2)g¯CHO (XIV) with an amine having the formula XII as illustrated above; or (9) alkylation of a sulphonamide having the formula XV or XVI Ar-SO2-NH-Y1-NR8-CHA1A2 (XV) Ar-NH-SO2-Y1-NR -CHA1A (XVI) to introduce an alkyl or substituted alkyl group R11 at the nitrogen atom marked with an asterisk; or (10) reductive amination of an alkanone containing 1 to 6 carbon atoms with an amine having the formula XVII; Ar-Z-Y1-NH-CHA1A2 (XVII) or (11) reduction of an amide or thioamide having the formula XVIII EMI7.1 and, where appropriate, removal of a removable protecting group. The process may also include removal of the acid from an acid addition salt to form the free base, metathetical displacement to convert one salt into another or neutralisation of the free base to form a salt. In order to prepare the compounds of the invention a sulphonylation reaction will normally be carried out at some stage of the synthesis. Where Y in the final product contains hydroxy, it may be recommended to protect the hydroxy group with a removable protecting group prior to sulphonylation to avoid sulphonylation at the hydroxy group. The hydroxy group is preferably protected by means of formation of its ester derivatives, for instance, acetate ester, which can be hydrolysed at any stage after the sulphonylation to restore the hydroxy group. The intermediate compounds used in steps (1) to (8) are known compounds or, where new, can be prepared by procedures within the skill of the medicinal chemist. The sulphonamides used in step (9) and the amines used in step (10) are novel compounds provided by this invention and can be prepared by steps (1) to (8). The amides and thioamides used in step (11) can be prepared from the corresponding amines having formula XVI in known manner. The reaction conditions used in the aforesaid process may be those conventionally used for the preparation of N-substituted thioamides or secondary and tertiary amines. In the case of the alkylation reactions the alkylating agent is suitably a compound having the formula P-Q where P is the substituted or unsubstituted alkyl group to be introduced and Q is a leaving group or atom, preferably halogen, advantageously chlorine or bromine. The alkylation of amines is normally carried out by reacting the amine with the alkylating agent in the presence of a suitable base. The base may be an inorganic base, for instance, an alkali metal carbonate, a tertiary amine, for instance triethylamine, or an excess of the amine reactant. The amine reactant may be used in the form of the amine as such or in the form of a salt such as an alkali metal salt. The alkylation of sulphonamides is generally effected under basic conditions such that the sulphonamide is in salt form. In the case of the sulphonylation reactions the sulphonylating agent is suitably a sulphonyl halide derivative, preferably the sulphonyl chloride of the appropriate sulphonic acid. Reductive amination of carbonyl compounds may be effected with catalytic hydrogen, nascent hydrogen or the Leuckart reaction. Thioamides may be reduced to amines with borane or in a two step procedure comprising alkylation with an alkyl halide followed by reaction with sodium borohydride. Amides may be reduced to amines with lithium aluminium hydride. Schiff's bases may be reduced to amines by catalytic hydrogenation. The following examples of procedures may be given to illustrate the synthesis of the compounds of the invention. An aromatic amine ArNRH is sulphonylated by reaction with C1-S02-Y1-C1 and the sulphonylation product Ar-NR-SO2-Y s is used to alkylate an aralkylamine A12 A CHNR H. This reaction sequence affords the N-arylalkanesulphonamide type of compounds of this series. The benzenesulphonamide type of compounds of this series may be produced by reaction of an appropriately substituted aromatic sulphonamide, for instance, Ar-S02-NH-CH(CH3)2, with C1-Y-NRCHA1A2; or by reaction of an aromatic sulphonyl halide with an omega-hydroxyalkylamine, optionally followed by N-alkylation, and replacement of the hydroxy group with a halogen and alkylation of the appropriate aralkylamine. The compounds of this invention exhibit Ca+2 antagonism in rabbit aortic smooth muscle when tested by a modified procedure from that described by Brockaert et al., Eur. J. Pharmacol., 53, 281 (1979). Here, transverse strips (10mm x 2.5mm) from the thoracic aorta were cut and suspended vertically in a jacketed (38 C - 50ml volume) organ bath in physiological saline solution (PSS) aerated with 95% 02/5% CO2. The composition of PSS was as follows (mM): NaCl 112, KCl 5, NaHC03 25, KH2P04 1, MgS04 1.2, CaCl2 2.5, dextrose 10. The lower end of each tissue strip was attached to a fixed post and the upper end to a Statham UC-4 transducer. Changes in force development were recorded on a Beckman Dynograph Polygraphic Recorder. Following equilibration, the muscles were contracted in a depolarizing solution of PSS in which 100 mM KCl was substituted for an equimolar concentration of NaCl. Following attainment of steady-state isometric force (20 min.), the test compound was added to afford a final concentration of 1 x l05M. The inhibitory effect, expressed as percent relaxation, was determined from the mean of two experiments twenty minutes after the addition of the compound being tested. In addition, the compounds of this invention demonstrate an inhibitory influence on arterial Ca - calmodulin dependent myosin light chain phosphorylation and subsequent contractile protein function when tested in standard experimental procedures for these inhibitory properties. As such, the compounds of the invention present an activity profile consistent with that of anti-arrhythmic agents, which utility was proven in vivo experiments in the standard experimental animal as follows: Rats weighing between 400-500 gms were anesthetized with 35-40 mg/kg Na pentobarbital i.p. Rats were closeclipped on the neck and left side prior to cannulation of the jugular vein and tracheotomy. In some experiments, a catheter was introduced into the carotid artery for measurement of arterial blood pressure. Respiration was provided by a Harvard Model 681 respirator at a rate of approximately 55/min and a volume of 4 cc per cycle. The rat was then placed upon its right side and the heart was exposed by making an incision and separating the ribs. 4-0 silk on taper RB-1 needle was passed under the left anterior descending coronary artery (LAD) at a location just under the tip of the left atrial appendage. The suture was left to be tied upon occlusion. Lead II ECG and cardiotachometer output were recorded on a Beckman R612. The rat was allowed to stabilize for several minutes before the administration of drug via the cannulated jugular vein. Compounds were suspended in carbowax, with total dose volumes kept below 0.20-0.25 ml. Fifteen minutes after dosing, the LAD was occluded by tying the suture. This procedure provokes severe ventricular arrhythmias, terminating in ventricular fibrillation and death in approximately 73 percent of animals given vehicle only. Data were analysed based on statistical analysis of heart rate fluctuations. Output from a Beckman cardiotachometer was digitised at 200 msec/pt using a Nicolet 3091 digital oscilloscope, and the data analysed to yield mean f variance of the rate for each 1 minute period (300 points). The measured variance for the period 5-11 minutes post-occlusion was well correlated with the severity of the observed ventricular arrhythmias, and provided a quantitive measure for the relative antiarrhythmic effectiveness of the compound being tested. For the purpose of these coronary ligation (C.L.) experiments, the actual mortality rate, expressed as a percentage of the animals employed, was obtained for purpose of comparison with the mortality rate of 73 percent in vehicle-treated animals. Thus, these data establish the compounds of this invention as Ca antagonists which are useful as antiarrhythmic agents functioning more at the vascular level than other known Ca+2 entry blockers. It has been observed that compounds of this invention inhibit arterial Ca+2- calmodulin dependent myosin light chain phosphorylation and subsequent contractile protein function. Based upon the activity profile elicited by the compounds of this invention in the above-described standard scientifically recognised test models, the compounds are established as anti-arrhythmic agents useful in the treatment of cardiac arrhythmias and conditions characterised by coronary arteries vasospasm. For that purpose, the compounds may be administered orally or parenterally in suitable dosage forms compatible with the route of administration, whether oral, intraperitoneal, intramuscular, intravenous, intranasal, buccal, etc. The effective dose range determined in the animal test models has been established at from 1 to about 50 milligrams per kilogram host body weight to be administered in single or plural doses as needed to relieve the arrhythmatic dysfunction. The specific dosage regimen for a given patient will depend upon age, pathological state, severity of dysfunction, size of the patient, etc. Oral administration is performed with either a liquid or solid dosage unit in any conventional form such as tablets, capsules, solutions, etc., which comprise a unit dose (e.g. from about 25 milligrams to about 4 grams) of the active ingredient alone or in combination with adjuvants needed for conventional coating, tableting, solubilising, flavouring or colouring. Parenteral administration with liquid unit dosage forms may be via sterile solutions or suspensions in aqueous or oleagenous medium. Isotonic aqueous vehicle for injection is preferred with or without stabilisers, preservatives and emulsifiers. Pharmaceutical compositions containing a compound of the invention in association or combination with a pharmaceutically acceptable carrier may be prepared by bringing the compound of the invention into association or combination with the carrier. The following examples illustrate the preparation of a representative number of compounds of this invention. After each example, the Ca +2 antagonist activity of the compound is presented in terms of percent relaxation (P.R.) at 10-5M concentration unless indicated otherwise. Similarly, the percentage mortality of standard experimental test animals upon coronary ligation (C.L.) is presented for comparison with the control mortality rate of 73 percent of animals receiving vehicle alone. EXAMPLE 1 N-(3,5-Dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl] rnethylamino -N- (1 -methylethyl ) -i -propanesulphonamide 3,5-Dimethoxyaniline (34.62 g, 0.226 mol) in xylene (500 ml) containing suspended sodium carbonate (12.0 g, 0.113 mol) was treated with 3-chloropropane sulphonyl chloride (40.0 g, 0.226 mol) added dropwise with stirring. Stirring was continued for twenty-four hours and the solvent was stripped to provide a black partially crystalline gum. Filtration through dry-column silica gel combined with crystallisation from ethyl acetate/hexane provided N- (3, 5-dimethoxyphenyl) -3-chloro-1 -propanesulphonamide (20g), m.p. 68-71 0C. N-(3,5-Dimethoxyphenyl)-3-chloro-1-propanesulphonamide prepared in the preceding paragraph (16.56 g, .057 mol) was dissolved in xylene (300 ml) containing potassium carbonate (7.86 g, .057 mol) and N-methylhomoveratrylamine (11.13 g, .057 mol) and the reaction mixture was warmed and stirred three days. Filtration, stripping of solvent and chromatography on dry-column silica gel (1100 g) with 5% methanol/ethyl acetate provided crude N-(3,5-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1propanesulphonamide (5.32g). The product of the preceding paragraph (2.49 g, .0055 mol) in dry dimethylformamide (70 ml) was treated with sodium hydride (60% in mineral oil) (0.22 g, .0055 mol) and the reaction mixture was stirred for one hour. Isopropyl bromide (0.677 g, .0055 mol) was added and the solution was stirred overnight. The reaction mixture was stripped and chromatography provided the title product (0.43 g) as a gum containing a trace of methylene chloride. Analysis for: C25H38SO6N2. 0. 2CH2Cl2 Calculated: C, 59.16; H, 7.56; N, 5.47. Found: C, 59.26; H, 7.59; N, 5.39. P.R. = 90 at 10 5M; 27 at 10 6M C.L. = 50% EXAMPLE 2 %N-(3,4-Dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]-N-(1-methylethyl)-1-propanesulphonamide The title compound was prepared by the method of the preceding Example with the exception that 3,4dimethoxyaniline rather than 3,5-dimethoxyaniline was employed as the starting material. Analysis for: C25H38 SO6N2 Calculated: C, 60.70; H, 7.74; N, 5.66. Found: C, 60.39; H, 7.96; N, 5.67. P.R. = 74 C.L. = 0% EXAMPLE 3 3-[[2-(3 r 4-Dimethoxyphenyl)ethyl]methylamino]-N-(1- methylethyl)-N-(3,4,5-trimethoxyphenyl)-1-propanesulphonamide 3,4,5-Trimethoxyaniline (38.3 g, 0.208 mol) in xylene (800 ml), containing a small amount of methylene chloride to maintain a solution, was treated with sodium carbonate (22.13g). Then 3-chloropropanesulphonylchloride (36.95 g) was added dropwise with stirring and stirring was continued overnight at room temperature. Cooling, filtration and evaporation provided a semisolid mass which was triturated with diethylether, filtered and the filtrate taken to dryness. Chromatography of the residue obtained from the filtrate was carried out on dry-column silica gel with 50-50 ethyl acetate/hexane. Trituration of the product with diethyl ether provided N-3,4,5-trimethoxyphenyl-3chloro-1-propanesulphonamide (13.09 g) m.p. 84-850C. N-3 , 4, 5-Trimethoxyphenyl-3-chloro-1 -propane- sulphonamide (13.06 g, .04 mol) in xylene (300 ml), sodium carbonate (3.18 g, .03 mol), caesium carbonate (3.25 g, .01 mol) and N-methylhomoveratrylamine (7.88 g, .04 mol) were heated together with stirring for four days. Cooling, filtering and stripping provided a crude product (21.60 g) which was triturated with diethyl ether and filtered. Chromatography on alumna with 4% methanol/ethyl acetate provided 3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-N (3,4,5-trimethoxyphenyl)-1-propanesulphonamide (6.0 g) as a gum, containing traces of dimethylformamide and ethyl acetate. 3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]-N- (3,4,5-trimethoxyphenyl)-1-propanesulfonamide (6,7 g, .0139 mol) in dry dimethylformamide (100 ml) was treated with sodium hydride, 60% in mineral oil, (0.555 g, .0139 mol) and the reaction mixture was stirred for 1 hour. 2-Bromopropane (1.71 g, .0139 mol) was added and the solution was warmed overnight. The reaction was then stripped, dissolved in methylene chloride, filtered and evaporated to a gum. Preparative high pressure chromatography provided the title compound (3.40 g). Analysis for: C26H40N2O7S Calculated: C, 59.52; H, 7.68; N, 5.34. Found: C, 58.76; H, 7.73; N, 5.34. P.R. = 62 C.L. = 8.3% A portion of the product of the preceding paragraph was crystallised from diethyl ether to provide a crystalline solid m.p. 65-670C. EXAMPLE 4 N-(3,5-Dichlorophenyl)-3-[[2-t3,4-dimethoxyphenyl)ethyl3 methylamino] -N- (1 -methylethyl) -1 -propanesuiphonamide The title compound was prepared from 3,5-dichloroaniline, following the procedures of the preceding examples. Analysis for: C23H 32N2O4SCl2 Calculated: C, 54.87; H, 6.41; N, 5.56. Found: C, 55.02; H, 6.24; N, 5.48. P.R. = 86 C.L. = 0% EXAMPLE 5 N-(3-Trifluoromethylphenyl)-3-[[2-(3,4-dimethOxyphenyl)- ethyl] methylamino] -1 -propanesulphonamide This compound was prepared from 3-trifluoromethylaniline by the preceding method. Analysis for: C21H27N2O4SF3 Calculated: C, 54.77; H, 5.91; N, 6.08. Found: C, 54.57; H, 5.58; N, 5.85. P.R. = 51 C.L. = 25% EXAMPLE 6 N-(3-Trifluoromethylphenyl)-3-[[2-(3,4-dimethOxyphenyl) ethyl]methylamino]-N-(1-methylethyl)-1-propanesulphonamide This material was prepared from the substance described in the preceding example by alkylation as in Example 3 and purified by chromatography. H NMR (CDCl3) -1.12 (d, 6, J=3.5Hz Me2) 2.30 (s, 3, -N-Me) 3.84 (d, 6, (OMe)2) 6.72 (m, 3, aryl), 7.56 (m, 4, aryl). Analysis for: C24H33N2 04 SF3 Calculated: C, 57.36; H, 6.62; N, 5.57. Found: C, 57.16; H, 6.67; N, 5.51. P.R. = 78.5 C.L. = 14% EXAMPLE 7 N-[3-[ [2-(3,4-Dimethoxyphenyl)ethyl]methylamino]propyl]-N- (1 -methylethyl) -3- (trifluoromethyl )benzenesulphonamide N-isopropyl-3-trifluoromethylbenzenesulphonamide (5.362 g, .02 mol) in dimethylformamide (30 ml) was treated with sodium hydride (60% in mineral oil), (0.802 g) and stirred for 2 hours. Then N-(3-chloropropyl)-3,4dimethoxy-N-methylphenethylamine (5.436 g, .02 mol) was added and the reaction mixture was heated overnight. Filtration and removal of solvent provided the crude product (6.95 g). Column chromatography and high pressure liquid chromatography provided the pure product (4.35 g) as a gum. 1H NMR (CDCl3) 1.15 (d, 6, J=3.5H, Me2) 2.25 (s, 3, N-Me) 3.84 (d, 6, (OMe)2) 6.76 (m, 3, Ar) 7.25 (m, 3, Ar). Analysis for: C24H33N2O4 SF3 Calculated: C, 57.36; H, 6.62; N, 5.57. Found: C, 57.44; H, 6.66; N, 5.48. P.R. = 86.6 C.L. = 33% EXAMPLE 8 N-l3-[[2-(3,4-Dimethoxyphenyl)ethyl3methylamino3propyl]-N- (1 -methylethyl)-3- (trifluoromethyl)benzenesulphonamide N-(3-chloropropyl)-N- (1-methylethyl)-3-trifluoromethylbenzenesulphonamide (23.4 g, .068 mol) and N-methylhomoveratrylamine (13.29 g, .068 mol) in xylene (250 ml) containing anhydrous potassium carbonate (4.68 g, .034 mol) and caesium carbonate (11.08 g, .034 mol) were heated and stirred for 2 days. The reaction mixture was cooled, filtered and stripped to provide a gum with a small amount of crystalline material evident. Solution in diethyl ether, filtration of the small amount of solid and concentration of the filtrate provided the crude product (32.91 g). Chromatography first on dry column alumina then silica gel provided the same product as in the preceding example (11.84 g) as a gum. EXAMPLE 9 3,4-Dichloro-N-l3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino] propyl] -N- (1 -methylethyl )benzenesulphonamide N-(3-Chloropropyl)-N-isopropyl-3,4-dichlorobenzene sulphonamide, prepared by reacting 3,4-dichlorobenzenesulphonyl chloride with 3-hydroxypropylamine followed by N-alkylation with 2-bromopropane and displacement of the hydroxyl group by chlorine, (13.94 g), N-methylhomoveratrylamine (8.23 g), K2CO3 (2.90 g) and Cs2CO3 (7.39 g) in xylene (300 ml) was heated and stirred for 5 days. The reaction mixture was cooled, filtered and stripped to provide a partially solid crude product which was stirred with diethyl ether, filtered and the filtrate stripped to provide 17.11 g. This material was chromatographed on dry-column silica gel (500 g) using ethyl acetate to provide the product which was recrystallised from diethyl ether-hexane to give the impure product (3.95 g) (m.p. 62-64 C). A second recrystallisation from diethyl etherhexane provided pure product (3.57 g, m.p. 65-66 C). Analysis for: C23H32N2Cl2O4S Calculated: C, 54.86; H, 6.41; N, 5.56. Found: C, 54.91; H, 6.20; N, 5.49. C.L. = 0% EXAMPLE 10 N-(3Z4-Dichlorophenyl)-3-[ E 2-(3,4-dimethoxyphenyl)ethyl3- methylamìno]-N-(1-methylethyl)-1-propanesulphonamide Following the procedures of the preceding examples with the exception that 3,4-dichioroaniline was employed as an initial reactant, N-(3,4-dichlorophenyl)-3-[[2-(3,4 dimethoxyphenyl)ethylgmethylamino]-1-propanesulphonamide was obtained. 4.23 g of this compound in dry DMF (40 ml) was treated with 6% NaH/mineral oil (0.267 g) and stirred for one hour. An appropriate amount of 2-bromopropane was added and the reaction was heated at Variac setting 25 overnight. The reaction was stripped to provide 6.13 g of a crude gum. The crude gum was dissolved in methylene chloride, washed with aqueous sodium bicarbonate, and the organic layer stripped. Chromatography provided the pure product (1.49 g) as a gum. Analysis for: C23 H 32N2 O4SCl2 Calculated: C, 54.87; H, 6.41; N, 5.56. Found: C, 54.74; H, 6.44; N, 5.43. C.L. = 40% EXAMPLE 11 N-(3,4,5-Trimethoxyphenyl)-3-[[1-(3,4,5-trimethoxyphenyl) ethylZamino]-1-propanesulphonamide 3-Amino-N-(3,4,5-trimethoxyphenyl)-1-propanesulphonamide was prepared from 3-chloro-N-(3,4,5-trimethoxyphenyl)1-propanesulphonamide. This material (3.04 g, .01 mol) and 3,4,5-trimethoxyphenyl acetone (2.10 g, .01 mol) was dissolved in absolute methanol (50 ml) containing platinum oxide (0.40 g) and shaken at 50 psi (3.45 bars) of hydrogen for 16 hours. After filtration and removal of solvent the residue was chromatographed on dry-column silica gel with 5% methanol-ethyl acetate to provide the product (2.47 g) as a partial ethyl acetate solvate. Analysis for C23H34O8S.O.5C4H8O2 Calculated: C, 55.23; H, 7.23; N, 5.15. Found: C, 54.82; H, 6.74; N, 5.29. C.L. = 40% EXAMPLE 12 3-[[(3,4-Dimethoxyphenyl)methyljmethylamino]-N-l3- (trifluoromethyl)phenyl]propanesulfonamide The title compound was prepared by reaction of 3-chloro-N-3- ( trifluoromethyl )phenyl-propanesulphonamide with N-methyl-3,4-dimethoxybenzylamine in xylene as in previous examples. Analysis for: C20H25N2O4SF3 Calculated: C, 53.80; H, 5.64; N, 6.27. Found: C, 53.34; H, 5.62; N, 6.04. C.L. = 40% EXAMPLE 13 N-[2-[[2-(3,4-Dimethoxyphenyl)ethyl]methylaminojethyl]-N- (1 -methyl ethyl ) -3,4 -dichlorobenzenesulphonamide The title compound was prepared by reaction of N-ss-chloroethyl-¯-(1-methylethyl)-3,4-dichlorobenzene- sulphonamide with N-methylhomoveratrylamine in xylene containing inorganic carbonate acid scavengers by heating for five days. Analaysis for: C22H30N2Cl204S Calculated: C, 53.99; H, 6.18; N, 5.72. Found: C, 53.94; H, 6.12; N, 5.74. C.L. = 0% EXAMPLE 14 3,4-Dichloro-N-[4-[[2-(3,4-dimethoxyphenyl)ethyl]methyl- amino]butyl] -N- (1 -methylethyl)benzenesulphonamide 3,4-Dichlorobenzene sulphonyl chloride (98.3 g) (0.4m) in methylene chloride (200 ml) was added dropwise to 4-amino-1-butanol (35.69 g) (0.4m) and diisopropyl ethylamine (51.75 g) (0.4m) in methylene chloride (500 ml). After workup crude 3,4-dichloro-N-(4-hydroxybutyl) benzene sulphonamide is obtained as a gummy white crystalline solid, m.p. 78-80 C. The compound was identified by combustion and spectral data. 3,4-dichloro-N-(4 hydroxybutyl)benzenesulphonamide (40.10 g) (0.134m) in dry dimethylformamide (400 ml) was treated with NaH/mineral oil/60% (5.38 g) (0.134m) and the reaction mixture was stirred one hour at room temperature. Then 2-bromopropane (16.5 g) (0.134m) was added and the reaction mixture heated at a temperature of 35 to 500C. over the weekend. The reaction mixture was worked up and the crude product chromatographed on dry column alumina (1 kg) with 1 to 1 ethyl acetate/hexane to provide 3,4-dichloro-N-(4 hydroxybutyl)-N-(1-methylethyl)benzenesulphonamide (16.09 g) as a light yellow oil. Pyridine-chromic acid complex was prepared by adding chromium trioxide (26.4 g) (94 m. moles) to pyridine (41.76 g) in methylene chloride (660 ml). The reaction mixture was stirred at room temperature for 3/4 hours. Then, 3,4-dichloro-N-(4-hydroxybutyl)-N (1-methylethyl) benzenesulphonamide (15.01 g) in methylene chloride (150 ml) was added all at once. After 1/2 hour the liquid was decanted and washed with 5% aqueous NaOH, 5% aqueous HCl, 5% aqueous NaHC03 and finally brine. After removal of solvent there was obtained 3,4dichloro-N-(1-methylethyl)-N-(4-oxobutyl)benzenesulphonamide as a dark oil (9.01 g) which started to crystallise nicely but was used below without further purification. 3,4-Dichloro-N-(1-methylethyl)-N-(4-oxobutyl)benzenesulphonamide (8.90 g) (.027m) and N-methyl-homoveratrylamine (5.29 g) (.027m) in absolute ethanol (100 ml) containing Pt02(0.6 g) was shaken under hydrogen (7 hours) and the reaction mixture was filtered and stripped to provide the crude product (13.32 g) as a dark greenish gum. This material was chromatographed, after removal of a small amount of insoluble solid, on dry column silica gel (500 gm) with 30% methanol/70% ethyl acetate to provide the title compound (7.26 g) as a clear white gum. Analysis for: C24H34N2Cl204S Calculated: C, 55.70; H, 6.62; N, 5.41. Found: C, 55.63; H, 6.59; N, 5.29. P.R.: = 688; C.L.: = 0%. EXAMPLE 15 N-[3- [ [2-(3 , 4-dimethoxyphenyl)ethyl]methylamino]propyl] -N- (1 -methylethyl ) -2,3, 4-trimethoxybenzenesulphonamide 2,3,4-trimethoxybenzenesulphonyl chloride (20.4 g) (0.765m) in methylene chloride (100 ml) was added dropwise to 3-aminopropanol (17.21 g) in methylene chloride (300ml). After stirring overnight the reaction mixture was washed with dilute aqueous HCl, dried and stripped to provide a solid. Trituration with diethyl ether provided N-(3 hydroxypropyl)-2,3,4-trimethoxybenzenesulphonamide (18.0 g) m.r. 95-970C. Analysis for: C12H19NO6 S Calculated: C, 47.20; H, 6.27; N, 4.57. Found: C, 46.89; H, 6.16; N, 4.57. N- ( 3-hydroxypropyl) -2,3,4 -trimethoxybenzenesulphon- amide (17.79 g) (0.58m) in dry dimethylformamide (100 ml) was treated with 60% NaH/mineral oil (2.31 g) (.058m) and then 2-bromopropane (2.31 g) (.058m) and heated with stirring overnight. Chromatography indicated only 50% reaction. Therefore the crude product was retreated using the same quantities to provide a crude product (23.84 g). Chromatography provided an alcohol, N-(3-hydroxypropyl)2,3,4-trimethoxy-N-(1-methylethyl)benzensulphonamide, (10.92 g) containing a trace of ethyl acetate. The alcohol was oxidised to the aldehyde, 2,3,4-trimethoxy-N-(1 methylethyl)-N-(3-oxopropyl)benzenesulphonamide, by use of the Cr03/pyridine reagent, prepared from CrO3 (18.84 g), pyridine (29.79 g) in methylene chloride (500 ml). The aldehyde was isolated as a dark gum (7.70 g). The aldehyde (7.50 g) (.0384m), N-methyl-homoveratrylamine (6.83 g) (0.350m) in absolute ethanol (100 ml) containing PtO2 (0.5 g) was shaken under hydrogen all day. The crude product (8.01 g) obtained from this procedure was subjected to chromatography to give the title compound as the pure product, a white gum (5.71 g). Analysis for: C20H40N207S Calculated: C, 59.52; H, 7.68; N, 5.34. Found: C, 59.29; H, 7.59; N, 5.20. P.R.: = 808; C.L.: = 0%.

Claims: CLAIMS 1. A compound having the formula: EMI23.1 in which Y is -(CH2)n where n is 1,2,3 or 4 or EMI23.2 EMI23.3 where R is hydrogen, alkyl of 1-6 carbon atoms, polyfluorinated alkyl of 1 to 6 carbon atoms, -CN, cyanoalkyl in which the alkyl moiety contains 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 4 to 8 carbon atoms; Rê, R3, R4, R5, R6 and R7, independently, are hydrogen, alkoxy of 1 to 3 carbon atoms, trifluoro methyl, -C1, -Br or -F; R8 is hydrogen or alkyl of 1 to 6 carbon atoms; R9 is alkyl of 1 to 3 carbon atoms; R10 is alkyl of 1 to 3 carbon atoms; m is O or 1; p is 0, 1, 2 or 3; and s is O or 1; or a pharmaceutically acceptable salt thereof, with the provisos that the sum of m, p and s must be 1,2,3 or 4; and the number of linear atoms in the bridge connecting the two aromatic rings does not exceed 9; and when n is 1 or 2, R2 R3 and R4 two of R2, R3 and are other than hydrogen. 2. A compound having the formula: EMI24.1 in which Z represents EMI24.2 where R is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; Rê, R and R4 are, independently, hydrogen, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; R5, R6 and R7 are, independently, hydrogen, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; n is 2, 3 or 4, with the proviso that when n is 2, two of R2, R3 and R4 are other than hydrogen; p is 1, 2 or 3; and R8 is alkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof. 3. A compound having the formula: EMI24.3 in which Z represents EMI25.1 where R is alkyl of 1 to 4 carbon atoms; R2 is hydrogen or alkoxy of 1 to 3 carbon atoms; R3, R4, R6 and R7 are, independently, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; n is 2, 3 or 4; and p is 1 or 2; or a pharmaceutically acceptable salt thereof. 4. A compound having the formula: EMI25.2 in which Z represents EMI25.3 where R is alkyl of 1 to 4 carbon atoms; Rê is hydrogen or alkoxy of 1 to 3 carbon atoms; R , R4, R6 and R7 are, independently, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; n is 2, 3 or 4; and p is 1 or 2; or a pharmaceutically acceptable salt thereof. 5. A compound having the formula: EMI26.1 in which Z represents EMI26.2 where R is alkyl of 1 to 4 carbon atoms; R2 is hydrogen or alkoxy of 1 to 3 carbon atoms; R , R4, R6 and R7 are, independently, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; n is 2, 3 or 4; and p is 1 or 2; or a pharmaceutically acceptable salt thereof. 6. A compound having the formula: EMI26.3 in which Z represents EMI26.4 where R is alkyl of 1 to 4 carbon atoms; R4, R6 and R7 are, independently, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, -Cl, -Br or -F; and p is 1 or 2; or a pharmaceutically acceptable salt thereof. 7. 3,4-Dichloro-N-[4-l[2-(3,4-dimethoxyphenyl) ethyl]methylamino]butyl-N-(1-methylethyl)benzene sulphonamide or a pharmaceutically acceptable salt thereof. 8. N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino] propyl]-N-(1-methylethyl)-2,3,4-trimethoxybenzenesulphonamide or a pharmaceutically acceptable salt thereof. 9. 3-[ [2-(3,4-Dimethoxyphenyl)ethyl]methylamino]- N-(1-methylethyl)-N-(3,4,5-trimethoxyphenyl)-1-propanesulphonamide or a pharmaceutically acceptable salt thereof. 10. 3,4-Dichloro-N-[3-[ [2-(3,4-dimethoxyphenyl) ethyl]methylaminozpropyl]-N-(1-methylethyl)benzene- sulphonamide or a pharmaceutically acceptable salt thereof. 11. A compound selected from N-(3,5-dichloro phenyl)-3-[[2-(3,4-dimethoxyphenyl)ethylgmethylamino]-N- (1 -methylethyl ) -1 -propanesulphonamide; N-(3-trifluoromethylphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methyl amino] -1 -propanesulphonamide; N-(3-trifluoromethylphenyl)3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-N-(1methylethyl)-1-propanesulphonamide; N-[3-[[2-(3,4 dimethOxyphenyl)ethylamethylamino]propyl]-N-(1-methylethyl)- 3-(trifluoromethyl)benzenesulphonamide; N-(3,4-dichloro phenyl)-3-[[2-(3,4-dimethoxyphenyl)ethylgmethylamino]-N- (1 -methylethyl) -1 -propanesulphonamide; N- (3,4, 5-trimethoxv- phenyl)-3-[[1-(3,4,5-trimethoxyphenyl)ethyl]amino]-1propanesulphonamide; N-(3,5-dimethoxyphenyl)-3-[[2-(3,4dimethoxyphenyl)ethyl]methylamino]-N-(1-methylethyl)-1propanesulphonamide; N-(3,4-dimethoxyphenyl)-3-[[2 (3,4-dimethOxyphenyl)ethylamethylamino]-N-(1-methylethyl)- 1-propanesulphonamide; 3-[[(3,4-Dimethoxyphenyl)methyl] methylamino]-N-[3-(trifluoromethyl)phenyl]-1-propanesulphonamide; N-[2-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino] ethyl]-N-(1-methylethyl)-3,4-dichlorobenzenesulphonamide; N-(3,5-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]-1-propanesulphonamide; N-(3,4-dimethoxy phenyl)-3-l[2-(3,4-dimethoxyphenyl)ethylZmethylamino]- 1-propanesulphonamide; 3-[[2-(3,4-Dimethoxyphenyl)ethyl] methylamino]-N-(3,4,5-trimethoxyphenyl)-1-propanesulphon- amide; N-(3,5-dichlorophenyl)-3-[ [2-(3,4-dimethoxyphenyl) ethyl]methylamino]-1-propanesulphonamide; N-(3,4-dichloro phenyl)-3-t[2-l3,4-dimethoxyphenyl)ethyl]methylamino]-1- propanesulphonamide; N-[2-[ [2-(3 ,4-dimethoxyphenyl)ethyl] methylamino]ethyl]-3,4-dichlorobenzenesulphonamide and the pharmaceutically acceptable salts thereof. 12. A compound as claimed in any one of Claims 1 to 11, for use as a pharmaceutical. 13. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 11 in association or combination with a pharmaceutically acceptable carrier. 14. Use of a compound as claimed in any one of Claims 1 to 11 for the preparation of a medicament for use as an anti-arrythmic agent. 15. A process for the preparation of a compound as claimed in Claim 1, which comprises (1) sulphonylation of an aromatic amine having the formula Ar-NHR (wherein R is as defined in Claim 1 and Ar is a group having the formula XIX EMI28.1 wherein R , R3 and R4 are as¯defined in Claim 1 to introduce the sulphonyl group having the formula II -S02-Y1-NR8-CHA1A (wherein YÚ is the same as Y save that if an hydroxy group is present in Y the hydroxy group may be protected by a removable protecting group; R is as defined in Claim 1, A1 represents hydrogen or alkyl of 1 to 3 carbon atoms and Aê represents such a group that AÚAêCH- is the same as formula XX EMI29.1 [where R5, R6, R7, R9, R10, m, p and s are as defined in Claim 1]); or (2) sulphonylation of an amine having the formula III * HNR-YÚ-NR8-CHAÚAê (III) (where AÚ, Aê, R, R8 and Y are as defined above) to introduce a sulphonyl group having the formula Ar-SO2- (where Ar is as defined above) at the nitrogen atom marked with an asterisk; or (3) alkylation of a sulphonamide having the formula Ar-SO2-NHR (IV) (where Ar and R are as defined above) to introduce a substituted alkyl group having the formula V -Y1-NR8-CHA1A2 (V) (where A1, A2, R8 and Y1 are as defined above); or (4) alkylation of an amine having the formula VI Ar-Z-YÚ-*NHR8 (VI) (where Z is as defined in Claim 1 and Ar, R8 and YÚ are as defined above) to introduce a substituted alkyl group having the formula -CHAÚAê (where AÚ and Aê are as defined above) at the nitrogen atom marked with an asterisk; or (5) reductive amination of a carbonyl compound having the formula 1A2C=O (VII) (where A1 and A2 are as defined above) with an amine having the formula VI as illustrated above; or (6) reduction of a Schiff's base having the formula VIII or IX Ar-Z-YÚ-N=CAÚAê (VIII) 12 (where AÚ, Aê, Ar, YÚ and Z are as defined above and q is 1, 2 or 3) or of an amide or thioamide having formula X or XI Ar-Z-YÚ-NR-CX-Aê (X) Ar-Z-(CH2)q-CX-NR8-CHAÚ-Aê (XI) (where A1, A2, Ar, R8, y1 Z and q are as defined above and X is O or S); or (7) alkylation of an amine having the formula XII HNR8-CHAÚAê (XIII) (where A1, A2 and R8 are as defined above) to introduce a substituted alkyl group having the formula XIII Ar-Z-YÚ- (XIII) (where Ar, Y and Z are as defined above); or (8) reductive amination of an aldehyde having the formula XIV Ar-Z-(CH2)q-CHO (XIV) (where Ar, Z and q are as defined above) with an amine having the formula XII as illustrated above; or (9) alkylation of a sulphonamide having the formula XV or XVI Ar-SO2-*NH-YÚ-NR8-CHAÚAê (XV) Ar-*NH-SO2-YÚ-NR8-CHAÚAê (XVI) (where AÚ, Aê, Ar, R8 and YÚ are as defined above) to introduce an alkyl or substituted alkyl group RÚÚ (where R11 is any meaning of R given in Claim 1 except hydrogen) at the nitrogen atom marked with an asterisk; or (10) reductive amination of an alkanone containing 1 to 6 carbon atoms with an amine having the formula XVII Ar-Z-YÚ-NH-CHAÚAê (XVII) (where AÚ, Aê, Ar, YÚ and Z are as defined above); or (11) reduction of an amide or thioamide having the formula XVIII EMI31.1 1 2 1 (where , , Ar, X, Y and Z are as defined above and R12 is hydrogen or alkyl of 1 to 5 carbon atoms) and, where appropriate, removal of a removable protecting group and, if desired, removal of the acid from an acid addition salt to form the free base, metathetical displacement to convert one salt. into another or neutralisation of the free base to form a salt, CLAIMS FOR P.JSTRIA 1. A process for the preparation of a compound having the formula: : EMI32.1 in which is -(CH2) n where n is 1,2,3 or 4 or EMI32.2 Z is EMI32.3 where R is hydrogen, alkyl of 1 co 6 carbon atoms, polyfluorinated alkyl of 1 to 6 carbon atoms, -CN, cyanoa]kyl in which the alkyl moiety contains 1 to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 4 to 8 carbon atoms; Rê, R , R4, R5, R6 and R7, independently, are hydrogen, alkoxy of 1 to 3 carbon atoms, trifluoro methyl, -Cl, -Br or -F; R8 is hydrogen or alkyl of 1 to 6 carbon atoms; R9 is alkyl of 1 to 3 carbon atoms; R10 is alkyl of 1 to 3 carbon atoms; m is O or 1; p is 0, 1, 2 or 8; and s is O or 1; or a pharmaceutically acceptable sal-t thereof, with the provisos that the sum of m, p and s must. be 1,2,3 or 4; and the number of linear atoms in the bridge connecting the two aromatic rings does not exceed 9; and when n is 1 or 2, two of R2, R3 and R4 are cther than hydrogen, which comprises: (1) sulphonylation of an aromatic amine having the formula Ar-NHR (wherein R is as defined above and Ar is a group having the formula XIX EMI33.1 wherein R2, R3 and R4 are as defined above) to introduce the sulphonyl group having the formula II -SO2-YÚ-NR8-CHAÚAê (wherein YÚ is the same as Y as defined above save that if an hydroxy group is present in Y the hydroxy group may be protected by a removable protecting group; R8 is as defined above, A1 represents hydrogen or alkyl of 1 to 3 A2 12 carbon atoms and A2 represents such a group that A A CH- is the same as formula XX EMI33.2 [where R5, R6, R7, R9, R10, m, p and s are as defined above]); or (2) sulphonylation of an amine having the formula III H*NR-YÚ-NR8-CHAÚAê (III) (where AÚ, Aê R, R8 and Y are as defined above) to introduce a sulphonyl group having the formula Ar-SO2- (where Ar is as defined above) at the nitrogen atom marked with an asterisk; or (3) alkylation of a sulphonamide having the formula Ar-S02-NHR (IV) (where Ar and R are as defined above) to introduce a substituted alkyl group having the formula V -Y1-NR8-CHA1A2 (V) (where Al Aê, R8 and YÚ are as defined above); or (4) alkylation of an amine having the formula VI Ar-Z-YÚ-N-HR8 (VI) (where Ar, R8, YÚ and Z are as defined above) to introduce a substituted alkyl group having the formula-CHA1 A2 (where A1 and A2 are as defined above) at the nitrogen atom marked with an asterisk; or (5) reductive amination of a carbonyl compound having the formula A1A2C=O (VII) (where AÚ and Aê are as defined above) with an amine having the formula VI as illustrated above; or (6) reduction of a Schiff's base having the formula VIII or IX Ar-Z-Y1-N=CA1A2 (VIII) Ar-Z-(CH2)q-C=N-CHAÚAê (IX) (where AÚ, Aê, Ar, YÚ and Z are as defined above and q is 1, 2 or 3) or of an amide or thioamide having formula X or XI Ar-Z-Y1-NR8-CX-A2 (X) Ar-Z-(CH2)q-CX-NR8CHAÚAê (XI) (where AÚ, Aê, Ar, R8, YÚ and Z are as defined above and X is O or S); or (7) alkylation of an amine having the formula XII HNR8 -CHA A (XII) (where A11 A2 and R8 are as defined above) to introduce a substituted alkyl group having the formula XIII; Ar-Z-Y - (XIII) (where Ar, YÚ and Z are as defined above); or (8) reductive amination of an aldehyde having the formula XIV Ar-Z-(CH2)q-CHO (XIV) (where Ar, Z and q are as defined above) with an amine having the formula XII as illustrated above; or (9) alkylation of a sulphonamide having the formula XV or XVI Ar-S02-NH-Y1-NR8-CHA1A2 (XV) * Ar-NH-SO2-YÚ-NR8-CHAÚAê (XVI) (where AÚ, Aê, Ar, R8, YÚ are as defined above) to introduce an alkyl or substituted alkyl group R11 (where RÚÚ is any meaning of R given above except hydrogen) at the nitrogen atom marked with an asterisk; or (10) reductive amination of an alkanone containing 1 to 6 carbon atoms with an amine having the formula XVII Ar-Z-YÚ-NH-CHAÚAê (XVII) AÚ, Aê, Ar, YÚ and Z are as defined above); or (where , , Ar, Y and Z are as defined above); or (11) reduction of an amide or thioamide having the formula XVIII EMI35.1 (where AÚ, Aê, Ar, X, YÚ and Z are as defined above and R12 is hydrogen or alkyl or 1 to 5 carbon atoms) and, where appropriate, removal of a removable protecting group and, if desired, removal of the acid from an acid addition salt to form the free base, metathetical displacement to convert one salt into another or neutralisation of the free base to form a salt. 2. A process for the preparation of a compound having the formula I EMI36.1 (where Y, n, Z, R, Rê, R3, R4, R5, R6, R7, R8, R9, R10, m, p and s are as defined in Claim 1) which comprises removal of an acid from an acid addition salt of a compound having the said formula I. 3. A process for the preparation of a pharmaceutically acceptable salt of a compound having the formula I EMI36.2 (where Y, n, Z, R, Rê, R3, R4, R5, R6, R7, R8, R9, R10, m, p and s are as defined in Claim 1), which comprises metathetical displacement to convert another salt of the compound having the formula I into the aforesaid pharmaceutically acceptable salt or neutralisation of the free base form of the compound having the formula I. 4. A process as claimed in any one of Claims 1 to 3, wherein the compound having the formula I or a pharmaceutically acceptable salt thereof is prepared for use as a pharmaceutical. 5. A process as claimed in any one of Claims 1 to 4, wherein Y is '(CH2) where n is 2, 3 or 4; Z represents EMI37.1 where R is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; is alkyl of 1 to 3 carbon atoms; m and s are both 0 and p is 1, 2 or 3. 6. A process as claimed in any one of Claims 1 to 3, wherein a compound having one of the formula Ia, Ib, Ic and Id EMI37.2 in which Z represents EMI38.1 where R is alkyl of 1 to 4 carbon atoms; Rê is hydrogen or alkoxy of 1 to 3 carbon atoms; R , R4, R6 and R7 are, independently, alkoxy of 1 to 3 carbon atoms1 trifluoromethyl, -Cl1 -Br or -F; n is 2, 3 or 4 and p is 1 or 2; or a pharmaceutically acceptable salt thereof is prepared. 7. A process as claimed in any one of Claims 1 to 3, wherein a compound selected from 3,4-dichloro-N [4-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]butyl]-N-(1methylethyl)benzenesulphonamide; N-[3-[[2-(3,4dimethoxyphenyl)ethyl]methylamino]propyl]-N-(1-methyl ethyl) -2,3, 4-trimethoxybenzenesulphonamide; 3-t[2-(3,4- dimethOxyphenyl)ethyl]methylamino]-N-(1-methylethyl)-N- (3,4,5-trimethoxyphenyl)-1-propanesulphonamide; 3,4dichloro-N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino] propyl]-N-(1-methylethyl)benzezesulphonamide and their pharmaceutically acceptable salts is prepared. 8. A process as claimed in any one of Claims 1 to 3, wherein a compound selected from N-(3,5-dichlorophenyl)3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-N-(1methylethyl)-1-propanesulphonamide; N-(3-trifluoro methylphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methyl- amino] -1 -propanesulphonamide; N-( 3-trifluoromethylphenyl) - 3-[[2-(3,4-dimethoxyphenyl)ethyllmethylamino]-N-(1- methylethyl)-1-propanesulphonamide; N-[3-[[2-(3,4dimethoxyphenyl)ethyl]methylamino]propyl]-N-(1-methylethyl)3-(trifluoromethyl)benzenesulphonamide; N-(3,4-dichlorophenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-N (1-methylethyl)-1-propanesulphonamide; N-(3,4,5-trimethoxy phenyl)-3-[[1-(3,4,5-trimethoxyphenyl)ethyl]amino]-1 propanesulphonamide; N-@3,@ @methoxyphenyl)-3-[[2-(3,4dimethoxyphenylAethy7]mr hylamino]-N-(1-methylethyl)-1- propanesulphonamide; N-(3,4-dimethoxyphenyl)-3-[[2 (3,4-dimethOxyphenyl)ethylJmethylamino]-N-(1-methylethyl)- 1-propanesulphonamide; 3-[[(3,4-dimethoxyphenyl)methyl3 methylamino]-N-[3-(trifluoromethyl)phenyl]-1-propane- sulphonamide; N-[2-[ [2-(3,4-dimethoxyphenyl)ethyl]methyl- amino]ethyl]-N-(1-methylethyl)-3,4-dichlorobenzene- sulphonamide; N-(3,5-dimethoxyphenyl)-3-[[2-(3,4-di- methoxyphenyl)ethyl]methylamino-1-propanesulphonamide; N-(3,4-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]-1-propanesulphonamide; 3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-N-(3,4,5-trimethoxyphenyl)-1propanesulphonamide; N-(3,5-dichlorophenyl)-3-[ [2-(3,4- dimethoxyphenyl)ethyl]methylamino]-1-propanesulphonamide; N-(3,4-dichlorophenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]-1-propanesulphonamide; N-[2-[ [2-(3,4- dimethOxyphenyl)ethyl]methylamino]ethyl]-3,4-dichloro- benzenesulphonamide and the pharmaceutically acceptable salts thereof is prepared. 9. A process for the preparation of a pharmaceutical composition in which a compound having formula I as illustrated and defined in Claim 1 or a pharmaceuticaily acceptable salt thereof is brought into association or combination with a pharmaceutically acceptable carrier. 10. Use of a compound having formula I as illustrated and defined in Claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use as an anti-arrythmic agent.

Inventors: BUZBY, GEORGE CARROLL
Applicants: AMERICAN HOME PRODUCTS CORPORATION
Application year: 1985
Main classification: C07C143
IPC codes: C07C311, A61K31