WO1991013865A1

WO1991013865A1 - Antiarrhythmic agents

Info

Publication number: WO1991013865A1
Application number: PCT/GB1991/000379
Authority: WO
Inventors: Edward William Gill; Derek Anthony Terrar; Sean Patrick Connors; Paul David Dennis
Original assignee: Isis Innovation Limited
Priority date: 1990-03-09
Filing date: 1991-03-11
Publication date: 1991-09-19
Also published as: EP0518939A1; JPH05505797A; GB9005318D0

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 blockers.

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 Williams¹. 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 well as leading to corneal microdeposits². Hence there is a need for selective class III

antiarrhythmics: such drugs would have potential beneficial impact on sudden cardiac death. 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 of class III antiarrythmic agents. Lis et al³. have reported that imidazolium analogues of sotalol show specific class III activity. Lumma et al⁴. have reported that the procainamide derivatives,

[(alkylsulphonyl)amino]benzamides, also show specific class III activity. Gwilt et al⁵. have reported a class III antiarrhythmic, UK 68798, which exerts its action by blockage of the delayed rectifier potassium current.

Morgan et al⁶. 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.

Gupta et al⁷. 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.

R₁ is a C₆-C₁₂ aralkyl or aralkenyl group which may carry 1 to 3 C₁-C₄ alkyl, alkenyl, alkoxy, haloalkyl or halogen substituents.

R₂ is C₁-C₆ alkyl, alkenyl, haloalkyl, C₆- C_{1 2} aralkyl or aralkenyl group which may carry 1 to 3 C₁-₄ alkyl, alkenyl, alkoxy, haloalkyl or halogen substitutents or

R₁ and R₂ may together with the N atom form a hetrocyclic ring selected from

wherein R is C₁-C₆ 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 R₁ and R₂ together form

then n is 1 to 3 and when R₁ and R₂ together form

and n is 1, R³ 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.

R¹ is preferably a hydrophobic phenyl alkyl group optionally substituted with one or more

hydrophobic substituents. Preferred substituents include halogen, haloalkyl or C₁-C₄ 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 R¹ in addition,other preferred groups are methyl, isopropyl or aralkyl.

R¹ and R² 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 R¹ and R² 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-methyl 3,4 dichlorophenylethylamino-2-propanol.

1 (4-nitrophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino -2-propanol

2g (10mmol) 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. (CDCl₃,ppm): 8.14, d, 2H,J=9Hz (Ar-NO₂) 6.80- 7.50m,5H 3.90-4.20m, 3H 2.45-3.00 m, 6H 2.40 s,3H (N-CH₃)

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

HCl. 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 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. (CDCl₃,ppm): 6.85-7.45m, 3H(ArCl₂) 6.60- 6.77m, 4H, (Ar)3.75-4.30 m,5H 2.50-3.00 m,6H 2.40 s,3H (N-CH₃)

1 -(4-4ethanesulphonamide 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 50mL ethylacetate and dried over magnesium 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 HCl 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. (CDCl₃,ppm): 7.0-7.5 m,5H (ArCl₂=Ar) 6.7- 7.0d,2H,J=9Hz (Ar) 5.80 s, 1H (broad -NHSO₂) 3.7-4.3 m,3H 3H 2.88 s, 3H (-SO₂CH₃) 2.50-3.15 m,6H 2.35 s,3H

(NCH₃) Analysis: Calculated for C₁₉H₂₄N₂O₄SCl₂.HCl.1H₂O:

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(CDCl₃,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 (1.0g) 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 C₂₅H₃₃NO₄ requires: C, 72.99; H, 8.03;N, 3.41.

Found: C, 73.4; H, 8.25; N, 3.4

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 (KCl disc): 1660 cm^-1

C₂₃H₂₆NO₆F₃ requires: 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. N.M.R. (CDCl₃,ppm) :8.17,d,2H, J = 9Hz (Ar-NO₂) 7.20,s,5H (Ar)6.91,d,2H,J=9Hz (Ar-NO₂) 3.90-4.20, m, 3H 2.30-3.00,m ,6H

Analysis: Calculated from C₁₇H₂₀N₂O₄ :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. (CDCl₃ppm) :8.17,d,2H, J=9Hz(Ar-NO₂) 7.38,m,5H

(Ar)7.20,m,5H, (Ar) 6.97,d,2H,J=9Hz, (Ar-NO₂)

4.98,4.92 both singlets

diff. isomers, (OCHN) 4.0-4.8,m,3H 2.5-3.0,m,6H

I.R.:-NO₂ 1590 cm^-1 (s), Lack of O-H, N-H

Analysis: Calculated for C₂₄H₂₄N₂O₄:C 71,2 H 6.00 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 H₂(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-amanophenoxy 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 CaCl₂(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 HCl was added. The solution was stirred for 1 hour and then washed with 2 x 50mL of ether. The water was 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, D₆-DMSO,ppm) :9.40 s,1H (broad, exchangeable NHSO₂)

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 (-OCH₂) 2.90-3.60 m,6H 2.80 s,3H

(SO₂CH₃)

Analysis: Calculated for C₁₈H₂₄N₂O₄S.HCl: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:

3-(4-chlorophenyl)-glutaric acid

70.0g 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 NaOMe/EtOH were added and refluxed for 18 hours. The evaporation residue was taken up in water, extracted into ether and acidified with 220 mL of concentrated HCl. The yellow solid was

recrystallized from ethylacetate/benzene to give 74.0g of solid, mp 164°C.

4-(4-chlorophenyl)-piperidine

48.5g of 3-(4-chloroρhenyl)-glutaric acid was dissolved in 80 mL 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 LiAlH₄ 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 mL 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 f i ltrate was dried and distilled. 11.3g of material came over at 115- 120°C, under 0.5 mmHg, with n^D ₂₃ = 1.5600.

3-(3,4-dichloroρhenyl)-glutaric acid

Procedure as for the monochlorophenyl analogue. 75.0g of 3,4-dichlorobenzaldehyde gave 49.3g of product after recrystallization from ethyl acetate/60-80° 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. 45.0g 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 C₁₁H₁₃NCl₂: 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 ₂₃ = 1.5740,

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 mL 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 (HCl salt) Calculated for

C₂₁H₂₇N₂O₄ClS-HCl: 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 (HCl salt) Calculated for

C₂₁H₂₆N₂O₄Cl₂S.HCl: C49.5; 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.

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, ⁸). Response was measured as the prolongation of the action potential at the 90% repolarization level (APD₉₀). An increase of

approximately 33% in APD₉₀ seems to be maximal, as this increase was elicited by almost complete

inhibition of the delayed rectifier potassium current, I_k . 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_k, 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 et al, ⁹ for a similar procedure). The effect of the present compounds on I_k was assessed from the extend of reduction of the outward tail current. A single- electrode voltage-clamp (electrodes containing

0.5 M K₂SO₄) was used for these experiments (Terrar & Mitchell, ⁸); 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. 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 N'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.

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. & Imoto, Y. (1987).

Pflugers Archiv 410, 596-603.

Claims

C LA I MS 1. Compounds of the formula I

R¹ is a C₆-C₁₂ aralkyl or aralkenyl group which may carry 1 to 3 C₁-C₄ alkyl, alkenyl, alkoxy, haloalkyl or halogen substituents.

R² is C₁-C₆ alkyl, alkenyl, haloalkyl, C₆- C₁₂ aralkyl or aralkenyl group which may carry 1 to 3 C₁ -₄ alkyl, alkenyl, alkoxy, haloalkyl or halogen substitutents or

R¹ and R² may together with the N atom form a hetrocyclic ring selected from

wherein R³ is C₁-C₆ 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 ¹ and R ² together form

then n is 1 to 3 and when R₁ and R₂ together form

and n is 1, R³ is not alkoxy or halogen.

2. Compound as claimed in claim 1, wherein R¹ or R² or both R¹ and R² are optionally substituted phenyl C₁-C₆ alkyl said phenyl group being substituted with 1 to 3 C₁-C₄ alkoxy, haloalkyl or halogen substitutents or phramaceutically acceptable salts thereof.

3. Compounds as claimed in claim 1, wherein R¹ and R² form a hetrocyclic ring of structure

wherein n is 1 to 3 and R₃ 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

wherein n is 1 and R³ 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