ANTIARRHYTHMIC AGENTS

Abstract: Phenoxypropanolamine derivatives of sotalol are described which exhibit specific class III antiarrhythmic activity with substantially no class II activity.

Description: Antiarrhythmic Agents The present invention is concerned with antiarrhythmic drugs in particular class III antiarrhythmic agents which are potassium channel bloc ers. It is generally accepted that ventricular arrhythmias are a significant factor in sudden cardiac deaths. Three main approaches are used to control reentrant ventricular arrhythmias. One is blockade of abnormal impulses using class I antiarrhythmic drugs. Secondly one can suppress ectopic foci which can trigger reentrant arrhythmias (class I and II drugs) . Thirdly one can increase refractoriness of the myocardium using class III antiarrhythmic drugs. These classifications for antiarrhythmic compounds are based on studies by Vaughan Williams . For example, drugs that increase the action potential duration (APD) and refractory period of cardiac muscle without any other significant effects are designated class III antiarrhythmics. The search for new class III compounds is important for several reasons. First of all thejre are only a very small number of compounds in this category and secondly the ones that exist are either too nonspecific or have serious clinical side effects. For example, amiodarone the most well known of the class III drugs can affect thyroid function and as 2 well as leading to corneal microdeposits . Hence there is a need for selective class III antiarrhythmics: such drugs would have potential beneficial impact on sudden cardiac death. SUBSTITUTESHEET Sotalol is a drug developed as a β-blocker (class II antiarrhythmics) in the 1960 ' s. It is nonspecific, has no intrinsic sympathomimetic activity and no membrane stabilising actions. However, Sotalol also lengthens repolarization and refractory period in all cardiac tissues independently of its antiadrenergic properties, although class III activity is much less than class II activity. There have recently been a number of reports 3 of class III antiarrythmic agents. Lis et al . have reported that imidazolium analogues of sotalol show 4 specific class III activity. Lumma et al . have reported that the procainamide derivatives, ( (alkylsulphonyl)amino]benzamides, also show specific class III activity. Gwilt et al . have reported a class III antiarrhythmic, UK 68798, which exerts its action by blockage of the delayed rectifier potassium current. Morgan et al . have attempted to obtain compounds having comparable levels of class II and class III activity by combining known β-blocking and class III pharmacophores via the amino moiety of each pharmacophore. 7 Gupta et al . have investigated a number of 3 methanesulphonamido phenoxy-2-hydroxy 1- aminoproopanes as CNS depressants and hypotensive agents. The present inventors have now prepared a series of phenoxypropanolamine derivatives of sotalol which exhibit a potassium channel blocking action and are consequently class III antiarryhthmics but which possess substantially no β blocking action. Accordingly the present invention provides compounds of the formula I wherein A is an acidic group, preferably a methanesulphonamyl or carboxyl group. R k «1 is a Cg-C-12 aralkyl or aralkenyl group which may carry 1 to 3 C 1 ~C 4 alkyl, alkenyl, alkoxy, haloalkyl or halogen substituents. R 2 is C.J-C, alkyl, alkenyl, haloalkyl, C 8 - C. j aralkyl or aralkenyl group which may carry 1 to 3 C.-. alkyl, alkenyl, alkoxy, haloalkyl or halogen substitutents or R. and R 2 may together with the N atom form a hetrocyclic ring selected from wherein R is C.-C- alkyl or alkenyl, optionally substituted with one or more halogen groups, alkoxy or halogen and n * 0-3 or pharmaceutically acceptable salt thereof with the proviso that when R. and R- together form then n is 1 to 3 and when R. and R 2 together form and n is 1, R is not alkoxy or halogen. The acidic group is preferably an alkylsulphonyl amide group most preferably methyl sulphonamide group which should be unsubstituted at the N atom. A further preferred acidic group is a carboxyl group. The acidic group is most preferably located in the 4- position, i.e. para position, but may be located in other positions, the 3- position for example. It is an essential feature of the present invention that the side chain amino group is a tertiary amine. This feature is essential in ensuring that the compounds of the present invention have essentially no β-blocking activity and also enhances potassium channel blocking potency. R is preferably a hydrophobic phenyl alkyl group optionally substituted with one or more hydrophobic substituents. Preferred substituents include halogen, haloalkyl or C.J-C. alkoxy substituents. Increasing hydrophobicity of the phenylalkyl group enhances potassium channel blocking potency of the compounds. R2 is also preferably a hydrophobic group and preferred groups are as for R 1 in addition ,other preferred groups are methyl, isopropyl or aralkyl. R 1 and R 2 may also together form a hetrocyclic ring. Preferred rings are Preferred substituents are C1-C4 alkoxy, haloalkyl or halogen, particularly preferred are dihalo substituted compounds. Compounds of the present invention were synthesised according to the reaction scheme shown in figure 1 wherein R^ and R- have the same meanings as above. Figure 1 also shows the reaction scheme for the synthesis of secondary amine compounds included for comparative purposes. The synthesis of the compounds of the present invention is further illustrated by the following example of the preparation of 1-(4- methanesulphonamide phenoxy) -3- (N-methy1 3,4 dichlorophenylethylamino-2-propanol. SUBSTITUTESHEET 1 (4-nitrophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino -2-propanol 2g (lOmmol) of N-methyl 3,4 dichlorophenylethylamine was dissolved in 25 mL of ethanol along with 2g (10.3mmol) of 1-(4-nitrophenoxy) -2,3 epoxypropane. The mixture was then refluxed for 12 hours and on cooling 0.93g (10.3 mmol) of oxalic acid in 10 mL of ethanol was added to the reaction mixture. On standing a white powder separated which was filtered and recrystallized from ethanol/ether. Yield 4.0g (8.2 mmol,82%) .m.p. 92-94°C. The free amine was obtained by addition of 20mL 1N NaOH and extraction with 2 x 100mL of ethylacetate. The organic layer was then dried over magnesium sulphate and the solvent removed under reduced pressure leaving the amine as a yellow oil. N.M.R. (CDC1 3 ,ppm): 8.14,d,2H,J=9Hz (Ar-N0 2 ) 6.80- 7.50m,5H 3.90-4.20m,3H 2.45-3.00 m,6H 2.40 s,3H (N-CII-) 1-(4-aminophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino) -2-propanol 1.4g (3.5mmol) of 1- (4-nitrophenoxy) -3-(N-methyl 3,4 dichlorophenylethylamino) 2-propanol was added slowly to rapidly stirring solution of 3g of iron powder in 20mL of ethanol and 2mL of concentrated HC1. The mixture was the refluxed for 4 hours and allowed to cool. After filtering off the iron the ethanol was removed under reduced pressure and 25mL of 1N NaOH was added slowly along with 50mL of B TIT TESHEET ethylacetate.. The aqueous layer was further extracted with 2 x 50mL of ethylacetate. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure yielding the amine as a lightly yellow oil. Yield 0.5g (1.4mmol,39%) . The amine was pure by TLC and used directly in the next stage without further purification N.M.R. (CDC1 3 ,ppm): 6.85-7.45m,3H(ArC1 2 ) 6.60- 6.77m, H, (Ar)3.75-4.30 m,5H 2.50-3.00 m,6H 2.40 s,3H (N-CH 3 ) 1-(4-methanesulphonamide phenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol 3.4g (11mmol) of 1-(4-aminophenoxy)-3-(N- methyl 3,4 dicholorophenylethylamino)-2-propanol was dissolved in 8 mL of dimethylformamide and cooled to 0°C in an ice bath. 0.90mL (12mmol) of methanesulphonyl chloride was then added and the mixture was left under a drying tube for 1 hour at 0°C. After this time the solution was left to slowly warm to room temperature over 2 hours after which 200mL of ether was added. An oil precipitated and after decanting the ether the oil was dissolved in 15mL of 2N NaOH. 50mL of ethylacetate was added and the aqueous layer was then extracted. The organic layer was further extracted with 2 x 10mL of 2N NaOH. The combined aqueous fractions were then neutralized with concentrated HCL to pH 7 causing an oil to precipitate. This aqueous solution was then extracted with 3 x 50ιnL ethylacetate and dried over magnesium SUBSTITUTESHEET sulphate. Removal of the solvent under reduced pressure yielded the product as a clear oil. The amine was converted to the hydrochloride by addition of 1 equivalent of concentrated HC1 in ethanol. Removal of the solvent left a glassy solid which could not be induced to crystallise and was pure by TLC. Yield 4.0g (8.3mmol, 76%). N.M.R. (CDC1 3 ,ppm): 7.0-7.5 m,5H (ArC1 2 =Ar) 6.7- 7.0d,2H,J=9Hz (Ar) 5.80 s, 1H (broad -NHS0 2 ) 3.7-4.3 m,3H 3H 2.88 s, 3H (-S0 2 CH 3 ) 2.50-3.15 m,6H 2.35 s,3H (NCH 3 ) Analysis : Calculated for Cj 9 H 24 N 2°4 SC1 2 ,HC1 * 1H 2 0: C45.5 H 5.44 N 5.58 S 6.38 Found: C45.8 H 5.9 N 5.9 S 6.2 The following example illustrates the synthesis of compounds according to the present invention wherein the methylsulphonamide group is replaced by a carboxyl group by synthesis of N(3(4 carboxyl phenoxy)-2-hydroxypropyl-4-phenyl piperidine trifluroacetate. 1.2 epoxy-3-(4-t,butoxycarbonyl phenoxy)-propane 4-hydroxy t.butyl benzoate (1.94g.) was dissolved in 10 mL of 1N sodium methoxide in methanol. The solution was evaporated and the solid residue was dissolved in dry dimethylformamide (10mL); epichlorhydrin (3 mL) was added and the mixture was maintained at 75°C for 18 hours. The reaction mixture was cooled, poured into 10% citric acid solution (40 mL) and extracted with ehtyl acetate. The organic layer was washed with water and saturated salt solution and dried (magnesium sulphate) . The solvent was removed and the residue was fractioned by flash chromatography on silica gel, eluting with methylene dichloride/toluene 1:1 v.v. The epoxy propane derivative was the first compound to elute, and crystallised on removal of the solvent. Yield 1.4g (56%) . m.p. 39°C. NMR(CDC1 3 ,ppm) : 7.9 (d, 2H) , 6.8 (d, 2H) , 4.1 (m, 2H) , 3.3 (m, 1H) , 2.8(m,2H) , 1.55{s,9H) . N- (3- (4-t.butoxycarbonyl phenoxy) -2-hydroxy-propyl) -4-phenyl piperidine The above epoxy propane derivative (I.Og) and 4-phenyl piperidine (0.65g) were dissolved in ethanol (6 mL) and the mixture was refluxed for 2 hours. On cooling the product crystallised. It was collected and recrystallised from ethanol. Yield 1.37g. m.p. 105°C C 25 H 33 N0 4 requires: C, 72.99; H, 8.03;N, 3.41. Found: C, 73.4; H, 8.25; N, 3.4 SUBSTITUTESHEET N-(3-(4-carboxyl phenoxy) -2-hydroxypropyl)-4-phenyl piperidine trifluoroacetate The above t.butyl ester (0.82g) was dissolved in trifluoroacetic acid (5 mL) and stood at room temperature for 1 hour. Dry ether (50 mL) was added and the white crystalline precipitate was collected. Yield 0.76g. m.p. 212-214°C. IR (KC1 disc): 1660 cm "1 C 23 H 26 N0 6 F 3 re S uireS: C,58.85; H,5.54; N,2.98. Found: C, 59.0; H, 5.65; N, 3.0. The synthesis of 1-(4-methane sulphonamide phenoxy)-3-(N phenyl ethylamino)-2-propanol is described as illustrative of the preparation of secondary amine derivatives used for comparative study. 1-(4-nitrophenoxy)-3-(N-phenylethylamino)-2-propanol 10g (51 mmol) of 1-(4-nitrophenoxy) -2,3 epoxypropane was dissolved in 100mL of ethanol along with 6.40 g (51 mmol) of 1-phenethylamine. The mixture was heated for 2 hours at 60°C after which the ethanol was removed under reduced pressure leaving a golden brown solution. Washing with 60-80°C petroleum ether yielded a yellow solid which was recrystallised from ethylacetate. Yield, 7.7g (24 mmol,48%), m.p. 104°C. SUBSTITUTESHEET N.M.R. (CDC1 3 ,ppm) :8.17,d,2H, J = 9Hz (Ar-NO-,) 7.20,s,5H (Ar)6.91,d,2H,J=9Hz (Ar-N0 2 ) 3.90-4.20, m, 3H 2.30-3.00, in, 6H Analysis: Calculated from C 17 H 2Q N 2 0 4 :C 64.5 H 6.39 N 8.86 Found . : C 64.3 H.6.5 N 8.6 2-phenyl-3-(N-phenylethylamino)-5-(4-nitrophenoxy methyl)oxazolidine 5g (15.8 mmol) of 1-(4-nitrophenoxy) -3-(N- phenylethylamino) -2-propanol was dissolved in 75mL of toluene along with 1.8mL (17.7 mmol) of freshly distilled benzaldehyde and 50 mg of p-toluene sulphonic acid. The mixture was then refluxed in a Dean Stark apparatus for 16 hours, cooled, and washed with 2 x 50mL of 1N sodium bicarbonate. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure yielding a yellow oil. The oil was washed with 3 x 50mL of 40-60°C petroleum ether and the combined extracts on cooling produced a white crystalline material. Yield, 4.6g (11 mmol, 72%). there was a partial separation of the stereoisomers on crystallisation giving rise to two different melting points: 64°C, 90-91°C, N.M.R. (CDC1 3 ppm) :8.17,d,2H,J=9Hz(Ar-NO_) 7.38,m,5H (Ar)7.20,m,5H, (Ar) 6.97,d, 2H,J=9Hz, (Ar-N0 2 ) 4.98,4.92 both singlets diff. isomers, (OCHN) 4.0-4.8,m,3H 2.5-3.0,m,6H I.R.:-N0 2 1590 cm '1 (s), Lack of O-H, N-H Analysis : Calculated for C 24 H 24 N 2°4 : 71 ,2 H 6,0 ° N 6 " 93 Found:C 71.2 H 6.1 N 6.8 2-phenyl-3-(N-phenylethylamino)-5-(4-aminophenoxy methyl) oxazolidine 1g (2.5 mmol) of 2-phenyl 3-(N- phenylethylamino) 5-(4-nitrophenoxy methyl) oxazolidine was dissolved in 30mL of ethanol along with 1mL of 2N NaOH and 100 mg 10% Pd/C. On shaking in 1 atm. of H 2 (g) there was a quantitative uptake of hydrogen within 40 minutes. The reaction mixture was then centrifuged and the solvent was decanted and evaporated under reduced pressure leaving a colourless opaque oil. This was then extracted with ether, washed with 2 x 50mL of water, dried over magnesium sulphate and the solvent removed leaving a colourless oil 0.90g (2.4 mmol,97%). The amine was pure enough to use directly in the mesylation. 1-(4-methanesulphonamide phenoxy)-3- (N-phenylethylamino)-2-propanol 0.90g (2.4 mmol) of 2-phenyl 3-(N- phenylethylamino) 5-(4-aminophenoxy methyl) oxazolidine was dissolved in 10mL of sodium dried ether and cooled to 5-10°C. The atmosphere above the solution was kept dry using a CaC1 2 (s) drying tube. A solution of 0.20mL (2.6 mmol) of methanesulphonyl chloride in 10mL of sodium dried ether was then added slowly and gradually a white precipitate formed. The solution was left for 12 hours warming to room temperature. The ether was decanted and 50mL of 1N HC1 was added. The solution was stirred for 1 hour and then washed with 2 x 50mL of ether. The water was SUBSTITUTESHEET removed under reduced pressure and the resulting solid was recrystallised from ethanol/ether giving the hydrochloride as fine white crystals, 0.50g (1.2 mmol,52%) .M.p.212-213°C. N.M.R. (Hydrochloride, D 6 -DMSO,ppm) :9. 0 s,1H (broad, exchangeable NHS0 2 ) 7.20 s,5H (Ar) 7.12 d,2H,J=9Hz (Ar) 6.83 d,2H,J=9Hz (Ar) 4.0-4.35 m, 1H, (CHOH) 3.70-4.00 m,2H (-OCH 2 ) 2.90-3.60 m,6H 2.80 s,3H (S0 2 CH 3 ) Analysis: Calculated for C 1 g H 24 N 2 0 4 S.HC1 :C 53.98 H 6.06 N 6.99 S 7.98 Found: C 53.6 H 6.2 N 6.8 S 7.7 Compounds W, 1-(4-raethanesulphonamide phenoxy) -2- hydroxy-propyl-3-(N-(4-chlorophenyl-4-piperadine) ) and compound Y, 1-(4-methanesulphonamide phenoxy) -2- hydroxy-propyl-3- (N- (3,4-dichlorophenyl-4-piperadine) ) were synthesised as follows: SUBSTITUTESHEET 3-(4-chlorophenyl) -glutaric acid 70.Og of 4-chlorobenzaldehyde was dissolved with gentle warming in 127 mL of ethylacetoacetate. 10 mL of piperidine was added and the solution left overnight in a 2L flask. 5 equivalents of NaO e/EtOH were added and refluxed for 18 hours. The evaporation residue was taken up in water, extracted into ether and acidified with 220 L of concentrated HC1. The yellow solid was recrystallized from ethylacetate/benzene to give 74.Og of solid, mp 164°C. 4-(4-chlorophenyl)-piperidine 48.5g of 3- (4-chloroρhenyl)-glutaric acid was dissolved in 80 L of 880 ammonia, evaporated to dryness and then heated in an oil bath for 4 hours at 170-180°C before standing overnight. Recrystallization from ethanol gave 22.3g of the succinimide (mp 174°C) . 22.3g of succinimide was dissolved in 200 mL of THF and added dropwise, over 1 hour, to 7.6g of LiAlH^ in 200 mL dry THF in an ice bath. This mixture was refluxed for 30 min prior to cooling in ice. Cautiously add 7.5 L water with vigorous stirring, followed by 7.5 mL of 15% NaOH(aq) and a further 20 mL of water, then magnesium sulphate, and the filtrate was dried and distilled. 11.3g of material came over at 115- 120°C, under 0.5 m Hg, with n D 2 3 » 1.5600. 3-(3,4-dichloroρhenyl)-glutaric acid Procedure as ' for the monochlorophenyl analogue. 75.Og of 3,4-dichlorobenzaldehyde gave 49.3g of product after recrystallization from ethyl acetate/60-80 o petroleum ether. The pale yellow solid had a melting point of 172°C. 4-(3,4-dichlorophenyl) -piperidine The procedure was as for the the monochlorophenyl analogue. 45.Og of the glutaric acid gave 28.8g of the succinimide. This was recrystallized from THF/water. to give a solid with a sharp m.p. of 233°C. Analysis calculated for C 11 H 1 3 C1 2 : C,51.2; H, 3.5; N, 5.4; Cl, 27.5. Found: C, 51.2; H, 3.4; N, 5.3; Cl, 27.2. 11.5g of final product distilled over at 130-135°C under 0.1 mmHg, n D 2 3 = 1.5740, SUBSTITUTESHEET 1- (4-methanesulphonamide phenoxy) -2-hydroxy-propyl-3-(N- (4-chlorophenyl-4-piperidine) ) and 1- (4-methanesulphonamide phenoxy)-2-hydroxy-propyl-3-(N- (3,4-dichlorophenyl-4-piperidine) ) The two chlorophenylpiperidines were added to the epoxypropane as described for 4-phenylpiperidine (leading to compound H) . The reduction of the nitro group, however, was effected under milder conditions than those employed for the non-chlorinated phenylpiperidine. 5 mmol of the nitrophenoxy compounds were taken up in 70 L ethanol and a smooth uptake of hydrogen was observed at atmospheric pressure over 200 mg of 10% Pd/C for 15 mins. The addition of methanesulphonyl chloride to each of the amines, gave compounds W and Y according to the same procedure utilized for compound H. Monochloro microanalysis (HC1 salt) Calculated for C 21 H 27 N 2°4 C1S - HC1: C ' 53.1 ; H, 5.9 ; N, 5.9 ; S, 6.7. Found: C, 53.1, H, 6.1; N, 5.6; S, 6.6. m.p. 215°C Dichloro microanalysis (HC1 salt) Calculated for C 21 H 26 N 2 0 4 C1 2 S - HC1: C-9.5; H, 5.3; N, 5.5; S, 6.3. Found: C, 49.5; H, 5.5; N, 5.7; S, 6.3. m.p. 228°C Examples of compounds of the present invention are given in Table 1. Table 2 shows examples of compounds used for comparative studies of the potassium channel blocking ability and β blocking activity of compounds of the present invention. SUBSTITUTESHEET Table 1 SUBSTITUTE SH Table 2 CHj-SOrN* Vθ A N —ζ Xβ= OH H CH_-SOJ-N-/~ O' Λ Y Λ* N —ζ- N — OH « ( SOTALOL ) SUBSTITUTE SHEET Pharmacological testing Pharmacological activity was assessed by the ability to prolong the action potential in isolated guinea-pig ventricular rayocytes stimulated with 2 ms rectangular current pulses at a frequency of 1 Hz (Terrar & Mitchell, ) . Response was measured as the prolongation of the action potential at the 90% repolarization level (APD gQ ) . An increase of approximately 33% in PD 9Q seems to be maximal, as this increase was elicited by almost complete inhibition of the delayed rectifier potassium current, I.. The response shown in Table 3 was expressed as a percentage of this maximal prolongation elicited by the dose(s) indicated. The delayed rectified potassium current, I. , was recorded by applying step depolarizations under voltage-clamp conditions, e.g. to +40 m V from a holding potential of -50 m V for 300 ms, and was measured as the size of the outward ' tail ' current on repolarization to the holding potential (see Matsuura g et al, for a similar procedure) . The effect of the present compounds on I. was assessed from the extend of reduction of the outward tail current. A single- electrode voltage-clamp (electrodes containing 0.5 M K 2 S0.) was used for these experiments (Terrar & Mitchell, ); in some cases niεoldipine (3 μM) was present in the external solution to block currents carried by calcium, and in others cells were injected with the calcium, and in others cells were injected with the calcium chelator BAPTA (1,2-bis(2- Aminophenoxy)ethane N,N,N',N'-Tetraacetic Acid) to suppress currents activated by increases in cytosolic calcium. SUBSTITUTESHEET β blocking activity was determined from the extent of reduction of the rise in heart rate elecited in pithed rat preparations in response to 0.1 ml of 0.1 μg/ml isoprenaline. Table 3 shows results obtained for the prolongation at the 90% repolarization level produced in isolated guinea pig ventricular cells by examples of compounds of the present invention. Table 4 shows results obtained with comparative compounds including sotalol and secondary amine derivatives and a dialkylamine derivative of sotalol compound V. A comparison of the 3, 4 dichloro (Q) and 3,4 dimethoxy (J) derivatives shows that increasing the hydrophobicity of the phenyl alkyl system enhances potassium blocking activity. This is also shown by comparison of comparative compound V, having a diethyl amino group with compound G having a pheny ether substitutent and which shows activity in order of magnitude greater than V. Similarly increasing the hydrophobicity of the second nitrogen substituent increases activity as shown by compounds (J) and (K) . Incorporation of the side chain nitrogen into a ring as in compounds H, I, L, R, U, W and Y does not result in a reduction in activity and indeed, further substitution of the ring may produce very potent compounds. Comparison of compounds H, W and Y shows increasing potassium channel blocking activity with increasing hydrophobicity of the tertiary amino group. There is in particular a surprising increas in activity from compound H to W. Chloro substitution of the phenyl of the phenyl piperidine group as in compound W results in an increase in activity of approximately 100 times compared to the unsubstituted group of compound H. Dichlorosubstitution as in compound Y further enhances activity. So far as the methanesulphonamide group is concerned it can be seen that 'methyl substitution of compounds D and E results in loss of activity. However the position of the group is not essential since compound L shows that the corresponding 3 substituted compound retains activity although with reduced activity although the 4- position is preferred. It was found that secondary amine derivatives retain β-blocking activity whilst the tertiary amine derivatives of the present invention have substantially no β-blocking activity. Figure 2 shows typical results obtained for compounds A and C, secondary amines, and compounds H, S and Q of the present invention. It can be seen that whilst a number of the secondary amines show potassium channel blocking activity these compounds also retain significant β blocking, class II, activity. Compound A, which is a known β blocking agent, optimizes β-blockade with a propanolamme side chain with an iPr nitrogen substituent. Compound C has a phenylethyl nitrogen substituent but still retains antiadrenergic activity. However on making the amine of the propanlamine side chain a tertiary amine as in compounds H, S and Q there is no blockage of β receptors. SUBSTITUTE SHEET Table 3 SUBSTITUTE SHEET Table 4 ( SOTALOL ) Y NH CH 3 -SOj- " γ H *N " * f Λ 0 ι' ,0H REFERENCES 1. Vaughan Williams, E.M. Symposium on Cardiac Arrhythmias Denmark: Astra, 1970, 449-472. 2. Nattel, S. and Talajc, M. Drugs, 1988, 36, 121-131. 3. Lis, R. Et. al. J. Med. Chem. 1987, 30(5), 696- 704. 4. Lumma, W. C. Jr. et. a. J. Med. Chem. 1987, 30(5), 755-758. 5. Gwilt, M. et. al. 1989 International Society for Heart Research Ann Arbor, Michigan, May 1989. 6. Morgan, T. K. et. al. 1989 Gordon Conference on Medicinal Chemistry. 7. Gupta, S. P. et. al. 1977 Indian J. Chem. 15B, 466. 8. Terrar, D. A. & Mitchell, M. R. (1987). In: Electrophysiology of Single Cardiac Cells, Noble, D. & Powell, T. (eds) , Academic Press. 9. Matsuura, H., Ehara, T. & I oto, Y. (1987). Pflugers Archiv 410, 596-603. T

Claims: C LA I MS Compounds of the formula I wherein A is an acidic group, preferably a methanesulphonamyl or carboxyl group. R 1 is a 6~C-j 2 aralkyl or aralkenyl group which may carry 1 to 3 C -C alkyl, alkenyl, alkoxy, haloalkyl or halogen substituents. R 2 is C1-C5 alkyl, alkenyl , haloalkyl, 05- C12 aralkyl or aralkenyl group which may carry 1 to 3 C1 -4 alkyl , alkenyl, alkoxy, haloalkyl or halogen substitutents or R 1 and R 2 may together with the N atom form a hetrocyclic ring selected from SUBSTITUTESHEET wherein R 3 is Ci -Cβ alkyl or alkenyl, optionally substituted with one or more halogen groups, alkoxy or halogen and n = 0-3 or pharmaceutically acceptable salts thereof, with the proviso that when R - and R-- together form then n is 1 to 3 and when Ri and R2 together form and n is 1 , R 3 is not alkoxy or halogen. 2. Compound as claimed in claim 1, wherein R 1 or R- or both R 1 and R- are optionally substituted phenyl C1-C alkyl said phenyl group being substituted with 1 to 3 C1-C4 alkoxy, haloalkyl or halogen substitutents or phramaceutical ly acceptable salts thereof. 3. Compounds as claimed in claim 1, wherein R 1 and R 2 form a hetrocyclic ring of structure SUBSTITUTESHEET wherein n is 1 to 3 and 3 is C1-C4 alkoxy, haloalkyl or halogen. 4. Compound according to any preceding claim, wherein the acidic group A is in the 4- position of the phenyl ring. 5. A compound according to claim 3, wherein the compound is W, 1- (4-methanesulphonamide phenoxy)-2- hydroxy-propyl-3-(N-(4-chlorophenyl-4-piperadine)) and compound Y, 1 -(4-methanesulphonamide phenoxy)-2- hydroxy-propyl-3-(N-(3,4-dichlorophenyl-4-piperadine)). 6. The use of compounds according to claims 1 to 5 in a medicament. 7. Compounds of the formula or SUBSTITUTE SHEET wherein n is 1 and R 3 is alkoxy ' or halogen and A has the same meaning as in claim 1 for use in the manufacture of a ' -medicament for the treatment of cardiac arrhythmia SUBSTITUTESHEET

Inventors: CONNORS SEAN PATRICK, DENNIS PAUL DAVID, GILL EDWARD WILLIAM, TERRAR DEREK ANTHONY, CONNORS, SEAN, PATRICK, DENNIS, PAUL, DAVID, GILL, EDWARD, WILLIAM, TERRAR, DEREK, ANTHONY
Applicants: ISIS INNOVATION, ISIS INNOVATION LIMITED
Application year: 1991
Main classification: C07D211
IPC codes: A61K31, A61P9, C07C217, C07C311, C07D209, C07D211, C07D215, C07D217, C07D295