IL86458A - Heterocyclic sulfonamido phenethylamine derivatives, their preparation and pharmaceutifal compositions containing them and intermediates therefor - Google Patents

Description

86458/2 ) n o>t? on mnp-n Hetrocyclic sulfonamidophenethylamine derivatives, their preparation and pharmaceutical compositions containing them PFIZER LIMITED C: 74793 86458/2 - 1 - This invention relates to certain sulfonamides which are antiarrhythmic agents, and to intermediates therefor.

The compounds of the invention prolong the duration of the action potential in cardiac, muscle and conducting tissue, and thereby increase refractoriness to premature stimuli. Thus, they are Class III antiarrhythmic agents according to the classification of Vaughan Williams (Anti-Arrhythmic Action, E.M. Vaughan Williams, Academic Press, 1980). They are effective in atria, ventricles and conducting tissue both in vitro and in vivo and are therefore useful for the prevention and treatment of a wide variety of ventricular and supraventricular arrhythmias including atrial and ventricular fibrillation. Because they do not alter the speed at which impulses are conducted, they have less propensity than current drugs (mostly Class I) to precipitate or aggravate arrhythmias, and also produce less neurological side effects. Some of the compounds also have some positive inotropic activity and therefore are particularly beneficial in patients with impaired cardiac pump function.

US 4581457 describes certain heterocyclic sulfonamide compounds as agents for treating inflammation, allergies and thrombosis. They are not described as anti-arrhythmic agents.

Thus the invention provides compounds of the formula: - (CH2) 2-N-CH2-Het (A) and their salts, where R is - 02» -NH2 or -NHS02(C1-C4 alkyl); R is C1-C4 alkyl;.

"Het" is a group of the formula:- where R is H, CH3. or C^; R is. -N02> -NH2, or -NHS02. (C1-C4 alkyl) ; and X is 0, S or NR4 where R4 is H or CH3; 3 with the proviso that when one. of R and. R is - 02, then the other is not -ΝΗ2· 3 The compounds of the formula (A) in which R and R are - HS02(C^-C4 alkyl) have activity as antiarrhythmic agents. The remaining compounds are synthetic intermediates.

Thus the 'invention also provides antiarrhythmic agents of the formula:- (CH ) -N-CH -Het. (I) and their pharmaceutically acceptable salts,, where R is alkyl) ; R1 is C1-C4 alk l; and · "Het" is a group of the formula:- where R is H,. CH3 or C^ . R is -NHS02(C--C4 alkyl);. and X is 0, S or NR4 where R4 is H or CH3.

In the compounds (I), R is preferably - HS02CH3> R1 is 2 3 preferably CH^ or C^H^, R is preferably H or CH^, R is preferably -NHS02CH3>" and X is preferably 0 or S. 3 \ The substituent R is preferably in the 6- or 7— position' when "Het" contains a quinolyl group, and in. the 5- or 6-position otherwise (i.e., when the benzene ring is fused to a 5_-membered. heterocycle);..

The preferred individual compounds have the formulae:- The- pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts- formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloride,, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate,, tartrate,, citrate, gluconate, benzoate, methanesulphonate,. besylate and p-toluenesulphonate salts. The salts are preparable by conventional techniques.

For assessment of effects of the compounds on atrial refractoriness, guinea pig right hemiatria are mounted in a bath containing physiological salt solution, and one end is connected to force transducer. Tissues are stimulated at 1 Hz using field electrodes. Effective- refractory period (ERP) is measured by introducing premature stimuli (S2 after every 8th basic stimulus (Sj) The- S JS J coupling, interval is gradually increased until S2 reproducibly elicits a propagated, response. This is defined, as the^ERP. The concentration of compound required to increase ERP by 25 (ED22) is ε^βη dete^ined.. ERP. is also measured in guinea pig. right papillary muscles incubated in physiological salt: solution. Muscles are stimulated at one end- using, bipolar, electrodes and the propagated electrogram is recorded at the opposite1 end viai a unipolar surface electrode. ERP- is determined as above using the extrastimulus technique. Conduction time is obtained from a digital storage oscilloscope by measuring the interval between the stimulus artefact and the peak, of the electrogram (i.e. the time required for the impulse to travel along the length of the muscle) ..

Atrial and ventricular ERP's are also measured in: anaesthetised or conscious dogs by the extrastimulus technique whilst the atrium or right ventricle is. being paced; at a constant rate..

The compounds of. the- formula (I) can be administered alone but will generally be administered i admixture with a pharmaceutical carrier selected with: regard to the- intended- route of administration and standard pharmaceutical practice.. They can be administered both to patients suffering from arrhythmias and also prophylactically to those likel to develop arrhythmias. For example they may be administered orally in the form of tablets containing such excipients as starch of lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

For administration to man in the curative or prophylactic treatment of cardiac conditions such as ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation, it. is expected that oral dosages of the compounds of the formula (I) will be in the range from 2 to 150 rag daily, taken in and up to 4 divided doses per day, for an average adult patient (70 kg) . Dosages for intravenous administration would be expected to be within the range\1.0 to 20mg per single dose as required. A severe cardiac arrythraia ^is preferably treated by the i.v. route in order to effect a rapid conversion to the normal rhythm. Thus for a typical adult patient individual tablets or capsules might contain 2 to 50mg of active compound,, in a suitable pharmaceutically acceptable vehicle or carrier. Variations may occur depending on the weight and condition of the subject being treated as will be known to medical practitioners. 86458/2 - 7 Thus the present invention provides a pharmaceutical composition comprising a compound of the formula (I) as defined above or pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable diluent or carrier.

The invention also provides the use of a compound of the formula (I), or ,of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or reduction o cardiac arrhythmias.

The compounds of the formula (I) can be prepared by the following general routes (1) The first route involves the acylation of a compound of the 3 formula (A) in which R and/or R is - H^. using a C^-C^ alkanesulphonyl chloride or bromide, or a C^-C^ alkanesulphonic 3 anhydride. When both R and R are -N^, clearly at least two equivalents of the acylating agent will be required and, of 3 course, R and R in the final product will be the same.

The reaction is typically carried out at room temperature,. and optionally in the presence of an acid acceptor such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid acceptor is particularly useful when an alkanesulphonyl chloride or bromide is used. It is in fact particularly convenient to carry out the reaction with an alkanesulphonyl chloride in pyridine. The product of the formula (I) can then be isolated and purified by conventional means.

The starting materials for this acylation reaction, are available conventionally, e.g. as follows r- (a) anic solvent ation (e.g. = 344 kPa) R R and "Het" are as defined for formula (I) , and Q is a leaving group such as chloro, bromo,. iddo or methanesulphonyloxy., (b) rganic solvent enation. i/344 kPa) R, Het and Q are as defined in (a) above. (c) Routes (a) and. (b) can also be carried out using starting materials in which the- substituent R on "Het" is nitro instead of C^-C^ alkanesulphonamido, thus producing, a- di-nitro intermediate which can be reduced by catalytic hydrogenation to a di-amino starting material, i.e^, a starting: material of the formula (A) in 3 which both R and R "are amino. and (d) (CH2) 2NHR Q-CH' -Het. (R" in Het = NO Reflux,: organic, solvent R (CH2) 2- -CH2-Het (R. = 02 Catalytic, hydrogenation (e.g. H-/Raney Ni/50 psi.

(C^-C^ alk l)S02NH-^^^- (CH2)2-N-CH2-Het (R3 = NH2) R is C^-C^ alkyl, "Het" in the first step is a nitro-substituted heterocycle as defined for formula (A),, and Q is a leaving group as defined in (a) above.

The starting materials- used in methods (a) to (d) are either known compounds or can be prepared by conventional techniques,, e.g. by the techniques illustrated in the following Preparations. / (2) The second route to the compounds (I) can be illustrated as follows :- (C1-C4 alkyl)S02NH (I) or (Cj^-^ alkyl)S02NH —^ ^-(CH2) 2~Q + R H-CH2-Het- Compounds (I): is C^-C^ alkyl, "Het" is as defined for formula (I), and Q, is a leaving, group such as chloro, bromo,. iodo,. alkanesulphonylox (preferably methanesulphonyloxy) ,. benzenesulphonyloxy or- toluenesulphonyloxy. The reaction is typically carried out in an. organic solvent at up' to the reflux temperature. It is preferred, to carry out the reaction "under reflux. The presence of an acid acceptor is optional but is most useful when Q is CI,. Br or I. Typical acid acceptors are pyridine,, triethylamirr , potassium carbonate and! sodium bicarbonate. The starting materials are again known compounds^ or can be obtained conventionally.' The following Examples, in which all temperatures are in °C,. illustrate the preparation of the compounds of the formula (I) :- EXAMPLE 1 N-Methyl-N-(3-methyl-5-methane8ulphonamidobenzofur-2-ylmethyl)-4- methanesulphonamidophenethylamlne Methanesulphonyl chloride (0.21 g,.1.85· mmole) was added; dropwise to a solution of N-methyl-N-(3'-methyl-5-aminobenzofur- 2-ylmethy1)-4-methanesulphonamldophenethylamlne (see Preparation; 10B - 0.78 g,. 1.68 mmole) in pyridine (7 ml) and the. solution was then stirred at room temperature for 60 hours. The: solvent was evaporated and the residue triturated, with toluene.. The toluene' was decanted,, the residue stirred, with aqueous sodium bicarbonate,., and the precipitate collected, by filtration and recrystalllsed'. from: methanol to give the title compound,, yield, 0.38 g,. m.p. 142-143.5°.

Analysis %;- Found: ' C.54.4;. Η.5.8;· N.9.1; Calculated, for c2iH27N3°5S2: C.54.2; H.5.85 N.9.O.. i EXAMPLE 2 N-Methyl-N-(5-methanesulphonamidobenzofur-2-ylmethyl)-4-methanesulphonamidophenethylamine Methanesulphonyl chioride (0.76. g, 6.6 mmole) was added dropwise to a solution of N-methyl-N-(5-aminobenzofur-2-ylmethyl)-4-aminophenethylamine (see Preparation 3 — 0.9 g, 3.0 mmole) in pyridine (25 ml) and the mixture' was stirred at room temperature for: 18 hours. The solvent was then evaporated and the residue diluted with aqueous sodium bicarbonate and extracted three, times with methylene chloride. The combined organic extracts were dried" (MgSO^) and evaporated, and the residue was purified by chromatography tin silica elutlng with ethyl acetate.

I The product-containing fractions were combined, evaporated and the resulting solid was recrystallised from ethyl acetate/methanol to-give the title compound, yield 0.35 g, m.p. 177-179°.

Analysis %:-Found : C.53.2;. H.5.7 N.9.0; Calculated for C»nH eN,0cS : C.53.2; H.5.6;; N.9.3.

EXAMPLE 3 N-Methy1-N-(5-methanesulphonamidobenzoxazol-2-ylmethyl)-4-methanesulphonamidophenethylamine- Methanesulphonyl chloride (0.38 g, 3.3 mmole) and N-methy1-N-(5-aminobenzoxazol-2-ylmethy1)-4-aminophenethylamine-(see Preparation 1C" - 0.45 g, 1.5 mmole) in pyridine (20 ml) when reacted together under conditions similar to those of Example 2. gave'the title compound,, yield, frout; ethanol 0.25 g,> m.p.,, 174-176°..

I " Analysis %;- Found: C.50..4;: H.5.1; N.12.4 Calculated for C^H^N^O^:. C.50.4; H,5,35;N,12.4.

EXAMPLE 4 N-Methyl-N-(6-methanesulphonamidobenzofur-2-ylmethyl)-4--methane8u- lphonamidophenethylamlne Methanesulphonyl chloride (0.21 g,. 1.8 mmole) and N-methyl-N-(6-aminobenzoftir-2-ylmethyl)-4-aminophenethylamine (see Preparation 2 - 0.24 g, 0.82 mmole) in pyridine (3 ml) when reacted together under conditions similar to those of Example 2,. gave the title compound as an oil,, yield, 0.18 g.

Analysis %:- Found:. C,53.<3;. H.5.7;. N.9.1 Calculated for C^H'^l^O^: C, 53.2s;; H.5.6; N,9.3 I EXAMPLE 5 N-Methyl-N-(6-methanesulphonamidoquinol-2-ylmethyl)-4- methanesulphamldophenethylamine Methanesulphonyl chloride (0.15 g, 1.3' mmole) and N-methyl-N-(6-aminoquinol-2-ylmethyl)-4-aminophenethylamine (see Preparation — 0.17 g,. 0.37 mmole) in pyridine (20 ml) when reacted together under\conditions similar to those of Example 2 gave the title compound, yield 0.70 g: from* ethyl acetate, m.p.'" 163-165°.

Analysis ;- Found: C',54.3; H„5.45;. N,12.1;.

Calculated for Ο-.Η-,Ν.Ο^: C.54.5; H.5.7;: N.12.1. 21 26 4 4 EXAMPLE 6 N-Methyl-N- [5-methanesulphonamido-2-benzo [b ] thienylmethyl]-4- methanesulphonamidophenethylamine Treatment of N-methyl-N- (5-amino-2-benzo [b ] thienylmethyl) — 4-aminophenethylamine (0.26 g - see Preparation 13) with raethane-sulphonyl chloride (0.23 g) in pyridine- according, to the method of. Example 2 gave the title compound, (0.167 g) ,r m.p. 175-177° .

Analysis ¾; — Found C, 50.99; H,5.39; N,8.93 Calculated- for- C-_H-oeN 0'.S,: C,51'.37; H,5.39;- N,8.99.

EXAMPLE' 7 N-Ethyl-N-(6-methane8ulphonamldoquinol-2-ylmethyl)-4- methanesulphonamidophenethylamine hydrochloride Methanesulphonyl chloride; (0.1 g,.1.29 mmole) was reacted with N-ethyl-N-(6-aminoquinol-2-ylmethyl)-4-methanesulphon- amidophenethylamine (see' Preparation.11B - 0.51 g, 1.23 mmole) in pyridine similarly to the procedure of Example 2,, giving the free. base of the title compound as a: gum. The gum was dissolved in- ethyl acetate and the solution was.' diluted with ethereal hydrdgen chloride and evaporated to dryness. The residue was triturated with ether- to, give the title compound as< a foam,, yield 0.06 g,, m.p. 96°.

Analysis :- Found: C',,50.2;. H.5.5; N',10.0;.

Calculated; for C22H28N404S2.HC1.H20:. C.49.75; H.5.9; N.10.5.

/ EXAMPLE 8 N-(6-Methanesulphonamido-2-quinolylmethyl)-N-methyl-4-methane- sulphonamidophenethylamine 4-[2-(Methylamino)ethyl]methanesulphonanilide (0.228 g,„ 1 tomol - see Preparation 14(B)) and 2;-chloromethyl-6-methane— sulphonamidoquinoline (0.135 g, 0.5 mmo - see Preparation 12(D)) were heated in; ethanol\solution (5 ml) at reflux for hours.. The' solvent: was then evaporated in vacuo and the residue' dissolved" in methylene chloride, washed with water,, dried: (MgSO^) ,. filtered, and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride containing: methanol (0% u to 1%) . The product-containing fractions were combined and: evaporated- in vacuo to give a foam which crystallised from ethanol, yield of the- title compound 0.45 g, m.p. 165-166°,. confirmed spectroscopically to be identical to the product of Example 5.' I The following Preparations, in which all temperatures illustrate the preparation of novel starting materials Preparation 1 (A) 2-Chloromethyl-5-nitrobenzoxazole 2-Amino-4-nitrophenol (10 g, 65 mmole) and ethyl chloroacetimidate hydrochloride (15.4 g„ 97.5 mmole) were heated: at reflux temperature in ethanol (100 ml) for 18 hours. The solvent was then removed by evaporation in vacuo and. the residue recrystallised from ethanol to- give the title compound,, yield.'" 9.0 g, m.p. 216-217°...

Analysis : Found : C.45.15; H.2.3;; N, 13.25,· Calculated for CoHcClN_0- :. C..45.2; H.2.4 N.13.2..

(B) N-methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethyl-amine 2-Chloromethyl-5-nitrobenzoxazole (2.85 g, 13.4 mmole), N-methyl-4-nitrophenethylamine (J.O.C., [1956], 21, 45) (2.2 g, 12.2 mmole) , potassium carbonate (1.85 g, 13.4 mmole) and sodium iodide (2.0 g, 13.4 mmole) were heated under reflux in acetonitrile (50 ml) for 3 days. The solvent was then evaporated, the residue diluted with water, and extracted three times with methylene chloride. The combined organic extracts were washed with water,, dried (MgSO^) , filtered and evaporated to dryness. The resultant oil was diluted with ether and the supernatant decanted and evaporated to dryness to give an orange solid, which was recrystalllsed fromi isopropanol to give the title compound, yield 0.80 g. Ή-N.m.r. (CDC1,): S = 8.6 (d, 1H); 8.3 (dd, 1H) ; 8.1 (d, 2H); 7.6 (d, 1H) ; 7.35 (d, 2H) 3.95 (s,, 2H) 2.95 (q, 2H) ; 2.85 (q, 2H);. 2.5 (s, 3H) p. p.m.

(C) N-Methyl-N-(5-aminobenzoxazol-2-ylmethyl) -4-aminophenethyl-amlne • N-Methyl-N-(5-nitrobenzoxazol-2-ylmethyl)-4-nitrophenethyl-amlne (0.78 g , 2.2 mmole) in ethanol (50 ml) containing Raney nickel (0.1 g) was stirred under a hydrogen atmosphere (50 psi = 344.7 kPa) for 18 hours, by which time thin layer chromatographic analysis showed that all the starting material had been consumed [silica chromatography plates using methylene chloride/methanol (19:1) as the solvent]. The reaction mixture was then filtered and evaporated to give an oil which was azeotroped with toluene and triturated with ether. The decanted ether was evaporated to give the title compound as an oil, which was used directly without further purification,, yield 0.45 g. Ή-N.m.r. (CDC13): 8 = 7.25 (d, 1H) ; 6.95 (dd, 3H) ; 6.65 (dd, 1H); 6.6 (d, 2H) ; 3.85 (s„ 2H); 2.7 (s, 4H) ; 2. (s, 3H) .

Preparations 2 to 4 The compounds of Preparations 2 and 3 were prepared similarly to Preparation 1(C) by the reduction of the' corresponing di-nitro compounds (see Preparations 6 and 5) using, t^/Raney Ni/ethanol/50 p.s.i./room temperature using reaction times of,- respectively,. 4 and 17 hours. The1 compound of Preparation 4 was prepared similarly to Preparation 1(C) but using R^/Vd/C in ethanol at 30 p.s.i. for 3 hours,, the relevant di-nitro starting material being the subject of Preparation 8. \ 0 p.s.i. is equivalent to 206.8 kPa, and 50 p.s.i. to 344.7 kPa.

Preparation 5 (A) 4-(Isopropylideneaminoxy)nitrobenzene A solution of propanone oxime (30 g, 0.4 mole) in dry tetrahydrofuran (300 ml)- was added slowly to a suspension of sodium hydride (10.8 g„ 0.45 mole) in dry tetrahydrofuran (50 ml).. After gas evolution was complete, dimethylsulphoxide (100 ml) and- 4-fluoronitrobenaene (57.85 g,, 0.41 mole) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted three times with ether. The combined ether extracts were washed with water, dried (MgSO^) and evaporated to give the title compound which was granulated, in tiexane and, filtered, yield 67 g. A sample (7 g) was recrystallised from ethanol,,. yield.5 g, m.p.. 104-106o;.

Analysis %:- Found: C.55.6; H.5.05; N.14.35;; Calculated for CQHinN,0,: C.55.7; H,5.,2; N.14.4.

(B) 2-Methyl-5-nitrobenzofuran 4-(Isopropylideneaminoxy)nitrobenzene (60 g, 0.309 mole) was added to glacial acetic acid (530 ml) containing gaseous, hydrogen chloride (25 g) and the mixture was^ heated at 100° for 18 hours. The solvent was evaporated and the' residue azeotroped with cyclohexane to give an oil which was diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with 10% aqueous sodium hydroxide solution and water, drJ^ed (MgSO^) and- evaporated to give the title compound,, yield, 46 g.. Axsample (5 g) was recrystallised from *" isopropanol, yield 2.5 g, m.p. 93-95°.

Analysis %:-Found: C',61.2;. H.4.1; Ν,.7.9; Calculated for CQH7N0_: C61.0;. H,4.0; N.,7.9.

(C) 2-Bromomethyl-5-nitrobenzofuran N-Bromosuccinimide (1.1 g,. 6.2 mmole) was added portionwise to a solution of 2-methyl-5-nitrobenzofuran (1..0 g, 5.6 tnmole) and benzoyl peroxide (50 mg)- in carbon tetrachloride (50 ml) and the reaction mixture was heated at reflux temperature- for 6 hours in the. presence- of bright light.. The reaction mixture, was then cooled, filtered, and the filtrate evaporated to dryness. The residue was recrystalllsed from petroleum ether to give the title compound yield 0.75 g, m.p. 96-98°.

Analysis %;- "\ Found: C.41.7; H.2.4;; N.5.3; Calculated for CftH,BrN0o: C 2..2;. H.2.4; N.5.5.

N-Methyl-4-nitrophenethylamine (0.41 g, 2.3 mmole) „ 2-bromomethyl-5-nitrobenzofuran (0.66 g, 2.6 mmole) sodium; iodide (0.39 g, 2.6 mmo e) and. potassium carbonate (0.36 g, 2.6 mmole) were heated at reflu temperature in acetonitrile (50 ml) for 8'· days. The solvent was then evaporated,, water was added,, and the mixture extracted three- times with methylene chloride.. The combined organic extracts were washed with water, dried (MgSO^) and evaporated to give a^semi-solid which was recrystallised from isopropanol to give the title compound,, yield 380 mg. 8.75 (s,. 1H); 8.3 (d, 1H) ; 8.2 (d,. 2H);, 7.-9' (d,: 1H) 7.6 (d, 2H);. 7.45 (s,.; 1H) 4.75 (t, 2H) ; 3.2. (t, 2H) ; 2.9 (s„ 2H) 2.5 (s, 3Η)-·..

Preparation 6 (A) 2-Bromomethyl-6-»nitrobenzofuran N-Bromosuccinimide ("NBS")' (1.11 g, 6.2 mmole) was- added to a solution of 2-methyl-6-nltrobenzofuran (1.00 g,, 5.65" mmole) and. azobisisobutyronitrile (20 mg) in carbon tetrachloride and. the mixture was heated at reflux temperature for 1½. hours' in the presence of" a bright light. The solvent was then evaporated and the residue dissolved in. methylene chloride, washed with water,, dried (MgSO^) , evaporated to dryness and purified' by column chromatography on silica* eluting with methylene chloride/hexane (7:3). The product-containing fractions were combined' and evaporated to give the title compound, yield 1.43 g. Ή-N.m.f'. clearly showed that the' product contained 20% of 2-dibromomethyl-6-nitrobenzofuran,. however, it was. not considered necessary to remove this and the product was used directly without: further purification..

I N-Methyl-4-nitrophenethylamine (0.84 g„ 4.7 mmole), 2-bromomethyl-6-nitrobenzofuran (1.2. g,. 4.7 mmole), sodium Iodide (0.7 g, 4.7 mmole) and potassium carbonate (0.71 g,: 5.2 mmole) were heated In acetonitrlle at the reflux temperature for 18 hours. The cooled reaction mixture was then filtered and the filtrate 'evaporated to dryness and purified by chromatography on silica elutlng with methylene chlorlde/hexane (1:1) followed by methylene chloride/methanol (19:1). The product-containing fractions were combined and. evaporated and the- residue was treated with decolourising charcoal in- ethanol to' afford: an oil which solidified: on standing.. Recrystallisation of the solid from ethanol/methylene chloride gave the title compound,, yield 0.27 g,-m.p. 69-69.5°V Analysis ¾:- Found: C.60.8; H.4.8 N.11.8 Calculated for ClgH17N305: C.60.8; H,4.8; N.11.8. Ή-n.m.r. (CDC1,) : & = 8.3 (s, 1H); 8.15 (dd, 1H) 8.1 (d, 2H); 7.55 (d, 1H) ;;. 7.35 (d, 2Η);·.6.65 (s, 1H) ; 3.8 (s, 2H) ; 2.95 (t, 3H); 2.75 (t, 3H) ; 2.4 (s, 3H).

Preparation 7 (A) 2-Hydroxymethyl-3-methyl-5-nitrobenzofuran 1 Molar diborane in vtetrahydrofuran (18.0 ml, 18.0 mmole'' was added dropwise to a suspension of 3-methyl-5-nitrobenzofuran-2-carboxylic acid (1.1 g, 5 mmole) in tetrahydrofuran at 0° .

Stirring was continued at 0° for 30 minutes then at room temperature for 18 hours when a second portion of diborane (5.0 ml) was added and the reaction' mixture was subjected to ultrasound for 2.5 hours. Methanol was then added cautiously to the. reaction, mixture and the solvent was removed by evaporation. The^ residue was taken. up in 'ethyl acetate, washed with aqueous sodium, bicarbonate, dried (MgSO^) the solvent removed by / - ' evaporation in vacuo and purified by column chromatography on silica eluting with methylene chloride.'■ The product-containing fractions were combined and evaporated to give the title compound,, yield 0.96 g. A sample was recrystallised. from ethyl acetate, m.p.. 149-150°.

Analysis %;- Found:. C.57..9;, H.4.2; N.,6.7; Calculated for C.-H-NO.: C.58,0; H.4.4; N.6.8., (B) 2-Chloromethyl-3-methyl-5-nitrobenzofuran Thionyl chloride (1.48 g, 12. mmole) was added dropwise to a solution of 2-hydroxymethyl-3-methyl-5-nitrobenzofuran (0.86 g, 4.15 mmole) in methylene chloride (10 ml) and pyridine (2 drops) and the mixture was stirred, at room temperature- for- 24 hours.. The reaction' mixture was, then diluted with water,, the organic phase separated,, and the aqueous phase; re-extracted wit methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate," dried and the solvent: evaporated to leave the title compound, 0.'93 g., A portion was recrystallised from- ethanol,- m.p. 141-142°.. j Analysis %;- Found: C..52.95; H.3.7; N,6,0; Calculated for C10HgClNO3: C.53.2; H.3.6; N.6.2.

Preparation 8 N-Methyl-N-(6-nitroquinol-2-ylmethyl)-4-nitrophenethylamine N-Methyl-4-nltrophenethylamine (0.39 g, 2.15 mmole) and 2-chloromethyl-6-nitroquinoline (0.40 g, 2.1, mmole) were heated at reflux temperature in ethanol (30 ml) for 6 hours. The solvent was then evaporated and the residue diluted, with 2M hydrochloric acid and extracted with methylene chloride. The aqueous layer was. basifled with aqueoUs sodium carbonate (to pH ^ 12) and extracted three times with methylene dhloride. These latter organic . / extracts were combined,, dried (MgSO^) and evaporated giving an oil which was purified by column chromatograph on. silica eluting with methylene chloride containing methanol (0% up to 1%) . The product-containing fractions were combined and evaporated to give a solid which was recrystallised from ethanol to give the title compound, yield 0.21 g,. m.p. 104-105°.

Analysis %:-Found: C.62.4; H.4.7;. N.15.2; Calculated for. CrnH, -N.0. : C.62.3; H.4.95;. N.15.3. 19· 18 4 4 8.9 (d, 1H) 8.5 (dd, 1H) ; 8.3-8.1 (m,. 3H); 7.6 (d, 1H) ; 7.35 (d,. 1H) 3.95 (s, 2H) ;, 3.0 (t„ 2H); 2.8 (t, 2H); 2.4 (a,. 3H) .

Preparation 9 (A) 4-MethanesilphonamidOphenethyl mesylate Methanesulphonyl chloride (146.6 g,, 1.28 mole) was added dropwise to a solution of 4-aminophenethyl alcohol (82.3 g, 0.6 mole) in pyridine (700 ml) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into water (700 ml) and the1 precipitate was collected by filtration, washed with water, dried and recrystallised from ethyl acetate to give the title compound, yield 31 g,. m.p. 134-136°. A further 14.5 g of product was obtained by concentration of the mother liquors in vacuo..

(B) N-Benzyl-N-ethyl-4-methanesulohonamidonhenethYlamine.-. 4-Methanesulphonamidophenethyl mesylate (10 g, 34 mmole) and N-ethylbenzylamine (10 ml, 67 mmole) were heated at reflu temperature' in ethanol (80 ml) for 3 hours. The solvent was evaporated,, the residue- taken; up in 2M hydrochloric acid and washed twice with methylene chloride.- The aqueous layer was basified with sodium bicarbonate (to pH ^ 12) and: extracted with / methylene chloride. The latter organic extract was dried (MgSO^) and evaporated to give an oil which solidified when triturated with diisopropyl ether. The solid was filtered off and discarded and the filtrate was evaporated in vacuo to give the title compound as an oil, yield 4.4 g. Ή-N.m.r. (CDC13) : & -■ 7.2 (a, 5H); 7.05 (s,. 4H) ; 3.6 (s, 2H); 2.95 (s, 3H) ; 2.70 (s,. 4H);: 2.40 (q,. 2H) ; 1.1. (t,. 3H) .

(C) N-Ethyl-4-methanesulphonamidophenethylamine N-Benzyl-N-ethyl-4-methanesulphonamidophenethylamine (4.3 g, 12.9 mmole) was stirred under a hydrogen, atmosphere (50 p.s.i. ■■· 344.7 kPa) in- ethanol (50 ml) containing 10% Pd/C (0.5 g) for 5 hours. The mixture was then filtered,, evaporated, and the residue- triturated with ether to give the title compound, yield 2.6 g„ m.p. 125-128°.

(CDC13/DMS0) : 8 7.06 (s, 4H); 4.9 (s, 2H) 2.86 (s, 2H);. 2.8 (s,. 2H); 2.65 (q, 2H) 1.05, (t, 3H) .

Preparation 1¾ (A) N-Methyl-N-(3-methyl-5-nitrobenzofur-2-ylmethyl)-4-methanesulphonamidophenethylamine \ N-Methyl-4-methanesulphonamidophenethylamine (1.66 g„ 7.3* mmole) and 2-chloromethyl-3-methyl-5-nitrobenzofuran- (see Preparation 7B - 0.82 g, 3.6 mmole) were: heated at reflux temperature in ethanol (20 ml) for 3 hours.. The solvent was then evaporated and the residue was purified by column' chromatography on silica eluting. with methylene' chloride/hexane' (4:1) followed by methylene chloride containing methanol (0% up to 5%) . The product-containing, fractions were combined; and evaporated,, and the residue was recrystallised. from' ethanol to give the title compound, yield 1.52 g, m.p. 124-124.5°.

PLC 441 Analysis %:-Found: C.57.7; H.5.65;. N.10.0 Calculated for C^H^N^S: C.57.5;. H.5.55; N.10.1. Ή-n.m.r. (CDC1,) :. & = 8.45 (d, 1H); 8.25 (dd,, lH) ;: 7.5 (d„ 1H);. 7.2 (q,. 4H) 3.8 (s, 2H); 3.05 (s, 3H) ; 2.9 (t, 2H) 2.75 (t, 2H); 2.4 (s, 3H) . 2.35 (s,. 3H) .

(B) N-Methyl-N-(3-methy-l-5-aminobenzofur-2-ylmethyl)-4-methanesulphonamidophenethylamine Catalytic hydrogenation of. the product of part (A) (0.7 g) similarly to Preparation 1(C) with a reaction, time of 4 hours gave the title compound (0.65 g) ., PLC 441 7.25 (m, 6H); 6.9 (d, 1H) ; 6.8 (dd, IE) 3.8 (s„ 2H) 2.95 (s, 3H); 2.9 (m...2H) ;: 2.7 (m, 2H) ; 2.4 (s, 3H);. 2.35 (s, 3H) .

Preparation 11 (A) N-Ethyl-N-(6-nitroquinol-2-ylmethyl) -4-methane- sulphonamidophenethylamine N-Ethyl-4-methanesulphonamidophenethylamine (see Preparation 9(C) - 1.7 g,; 7.0 mmole) vand 2-chloromethyl-6-nitroquinoline (0.'78 g, 4.1 mmole) were heated at. reflu temperature in ethanol (50 ml) for 4 hours. The solvent was then evaporated and the residue was diluted with aqueous sodium: bicarbonate and extracted: with methylene chloride.. The organic layer was dried (MgSO^) , evaporated and the residue was purified by column chromatography o silica eluting with methylene chloride. The product-containing fractions were combined and evaporated to give: the title compound as an oil, yield 0.56 g... 1 I I Ή-N.m.r. (CDC1J: § 8.6 (d,. 1H); 8.3-8.0 (m, 2H) ; 7.6 (d, 1H); 7.1 (3, 1H); 7.0 (s, 4H); 3.9 (s, 2H); 2.9 (s„ 2H) ; 2.7 (s, 2H); 2.65 (q, 2H) ;: 1.05 (t, 3H)..

(B) N-Ethyl-N-(6-aminoqulnol-2-ylmethyl)-4-methanesulphonamido-phenethylamlne The product of part (A) (0.55 g) was catalytlcally hydrogenated similarly to Preparation 1(C) but using H2 over 5% Pd on C in ethyl acetate at 15 p.s.i- (103.4 kPa) for 3 hours,, giving: the title compound (0.51 g) . 7.7 (d, 1H); 7.5 (d, 1H) ; 7.15 (d, 1H); 6.9 (broad s, 5H) ; 6.65 (d, 1H); 3.75 (s, 2H) ; 2.95 (s, 3H); 2.6 (s, 4H);, 2.5 (q, 2H) 0.95 (t, 3H).

Preparation 12 (A) 6-Amino-»2-methylqulnoline 2-Methyl-6-nitroquinoline (18.8 g) was stirred under a hydrogen atmosphere at 30 p.s.l. (equivalent to 206. 8 kPa) for 2. hours in ethanol solution containing 5% Pd/C. The catalyst was then removed by filtration,, the filtrate evaporated to small volume in. vacuo , and the ^resultant precipitate collected by filtration, washed with ethanol and ether,, and dried to* give: the title compound,, yield 13.2 g,. m.p. 188-189°.

Analysis ¾;-Found : C,.75..7r H.6.4; N.17.6 Calculated for C.nHinN_: C75.9; H.6.4; N.17.7.

/ (B) 6-Methanesulphonamido-2-methylquinoline Methanesulphonyl chloride (6.2 ml) was added dropwise to a stirred solution of 6-amino-2-methylquinoline. (12.5 g) in pyridine (100 ml) cooled to 5°. Stirring was continued for 17 hours, at room temperature. The pyridine was then removed by evaporation in vacuo,- the residue diluted with aqueous sodium bicarbonate,, and extracted three .times with methylene chloride. The combined organic extracts were combined', dried (MgSO^) and evaporated, in vacuo to give the title compound, yield 13.0 g, m.p. 151-153°.

Aalysls \ Found: v C.55.4; H.5.2;. N.11.6; Calculated, for C"..H. -N„0 S: C.55.9;; H,5.,l;: N,11.9v (C) 6-Methanesulphonamido-2-methylquinoline-l-oxide m-Chloroperbenzoic acid ("MCPBA") (5.2 g) was added portionwlse to a solution of 6-methanesulphonamido-2-methyl-quinoline (6 g) in methylene chloride and stirring was continued for 17 hours. The reaction mixture was then, diluted with aqueous sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with methylene. chloride. The combined organic layers were washed with aqueous sodium bicarbonate, dried (MgSO^) and evaporated in vacuo to give a solid which was recrystallised from ethanol to give the title compound,, yield 1.6 g, m.p. 241-243°..

Analysis %:- Found: C.52.5; Η,.4.95;, N.11.0, Calculated for C^H^N^S: C,52.4 H.4.8 N.ll.l.

(D) 2-Chloromethyl-6-methanesulphonamidoquinoline enesulphonyl. chloride- C1CH2' 6-Methanesulphonamido-2-methylquinoline-l-oxide (1.65 g) and j>-toluenesulphonyl chloride (1.72 g) were heated under reflux for 1 hou in 1,2-dichloroethane solution,, and the reaction mixture was then stood at room temperature for 17 hours. The reaction mixture was then- washed twice with aqueous sodium bicarbonate,, dried (MgSO^). and evaporated in vacuo. The residue, was purified by column, chromatography on silica eluting: with methylene chloride containing methanol (0% up to 1%) . The. product-containing, fractions were combined and evaporated to give a gum which solidified when triturated: with ether. Recrystallisation from toluene gave the' title compound , yield 0.75 g, m.p., 160-162°.

Analysis Found:. C.49.3; H.3.9; Ν,.10.1; Calculated for C C.48.8;: H.4.1;. N.10.35.

Preparation 13 (A) 2-Chloromethyl-5-nitrobenzo [b ] thiophene Thionyl chloride (1.0 ml) was added dropwise to a stirred mixture of 5-nitrobenzo[b]thiophene-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml). The solution was stirred at room temperature for 4 hours and then washed with water followed by aqueous sodium bicarbonate solution, and then dried . The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave a solid which was crystallised from ethyl acetate to give the title compound (0.73 g) , m.p.. 110-112°, used directly in the next stage.

(B) N-Methyl-N- [5-nitro-2-benzo [b] thienylmethyl]-4-nitrophenethylamine A mixture of the product of part (A) above (3.20 g) , N-methyl-4-nitropheftethylamine (2.52 g) , anhydrous potassium carbonate (4.0 g) and acetortitrile (40 ml) was heated under reflux with stirring for 20 hours and then cooled and filtered The - /' residue was washed with acetonitrile, and the combined filtrate and washings were evaporated to give an oil which was chromarographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product.. The product-containing fractions were, evaporated to give the title compound (4.17 g) , m.p. 76-78° (from isopropanol) .

Analysis %:- Found: C.57.8; H.4.4; N.U.I; C18H17N3O^S requires: C,58.2; H.4.6; N.11.3.

(C) N-Me hyl-N-[5-amino-2-benzo [b ] thienylmethyl]-4-aminophenethylamine A mixture of the> product of (B) above' (1.0 g) and stannous chloride dihydrate (6.07 g) in ethanol (100 ml) was heated under reflux for 8 hours and then evaporated. An excess of 20%" aqueous, sodium hydroxide solution was added and the mixture was extracted several times with dichloronlethane. The combined, organic extracts were -washed with water, dried and evaporated to, give an ! oil which was chromatographed on silica gel. Elution with dichloromethane/methanol (99:1) gave impurity and then further elution with dichloromethane/methanol (98:2) gave,: after collection and evaporation of appropriate fractions, the. product as an oil (0.30 g) which was used immediately in the procedure of Example 6.

Preparation 14 (A) 4-[2-(Methanesulphonyloxy)ethyl]-methanesulphonanilide Methanesulphonyl. chloride (50 ml) was added dropwise over' 0.5 hours to a stirred solution of 4-aminophenethyl alcohol (41.15 g) in pyridine (350 ml) at 0°. The mixture was allowed to warm to room temperature and stirred overnight.. The; mixture was then poured onto water (700 ml) from* which an orange solid, crystallised. After filtration, the solid was dissolved in methylene chloride, dried over magnesium sulphate, filtered and the filtrate re-evaporated. Crystallisation of the resultant solid from ethyl acetate: gave the title compound,.45.5 g,. m.p. 136-137°.

Analysis ¾:- Found: C.40.6 H.5.2;. N.4.9; Calculated for C10HI5NO5S'2: C.40.9; H.5.15; N.4.8.

(B) 4- [2-(Methylamino) ethyl]methanesulphonamilide To a solution of 4-[2-(methanesulphonyloxy)ethyl]methane-sulphonanilide (10.3 g-χ in ethanol (20 ml) was added a. solution of methylamine in industrial methylated spirits (30 ml of 33% solution). The mixture was heated with stirring at 85° in a pressure vessel for 17 hours. After cooling, the resultant solution, was evaporated to dryness, the residue' dissolved, in water, and the resultant solution basified' by the addition of sodium hydroxide (1.4 g) in water (12 ml) ., Evaporation- gave a off-white solid which was chromatographed on silica ("Kieselgel 60" - Trade Mark) eluting with methylene chloride/methanol (3:1)-Collection and evaporation df suitable fractions gave aa off-white solid (4.8 g) which crystallised from ethyl acetate/methanol to give- the title compound, 1.8 g. , m. p., 133-135°.

Analysis %:- Found:. C,52.5; H.7.1 N.12.2; Calculated for C10H16N2°2S: C.52.6; H.7.1;. N.12.3.

Abstract Title: "Antiarrhythmic Agents" Compounds of the formula:- and: their salts,. where R is -NHS02 (C^-C^ alkyl) , - H2 or - 02 R1 is- Cj-C^ alkyl; and "Het' is; a group of the formula:- 2 where R is H,. CH^ or C^ .

R3 is - HS02 (Cj-C^ alkyl), -NH2 or -N02, and X is 0,. S or NR4 where RA is H or CH3;. 3 with the proviso that: when one of R and R is -N02» then the other is not - H2«. 3 The compounds of the formula (A) in which both R and R are - HS02(C^-C^ alkyl) are antiarrhythmic agents. Thej reamining compounds ofline formula (A) are synthetic intermediates.- I I

Claims (12)

1. A compound of the formula:- or a salt thereof, where R Is -NHSO (Ci.-C, alkyl) , -NH or -NO-; R is alkyl; and "Het" is a group of the fonnula:- where R is H, CH^ or C^; R3 is - HS02(C1-C4 alkyl), -NH2 or -NC>2 4 4 and X is 0, S or NR where R is H or CH^; 3 with the proviso that when one of R and R is -NO is not -NH., . Si-

2. A compound as claimed in claim 1 wherein R is -NHS02CC1-C^ alkyl) and R" is -NHS02 (C-^-C^ alk l) , or a pharmaceutically acceptable salt thereof.

3. A compound as claimed in claim 2, wherein R is -NHS02CH3; R1 is CH3 or C^; and "Het" is a group of the formula: - where R is H or CH^. X is 0 or S; and R , which is attached to position a or b of "Het", is

4. A compound as claimed in claim 3 which has the formula: 86458/3 - 52 -

5. A pharmaceutical composition comprising a compound as claimed in any one of claims 2 Co 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

6. A compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof for use as a medicament.

7. A compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof for use as a medicament for prevention or reduction of cardiac arrhythmias.

8. The use of a compound as claimed in any one of claims 2 to 4, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the prevention or reduction of cardiac arrythmias substantially as described in the specification.

9. Ά compound of the formula (A) given and defined in Claim or a salt thereof, which is any one of those specifically hereinbefore mentioned.

10. A process for preparing a compound of the formula (A) giv and defined in Claim 1 or a salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples and Preparations.

11. A compound of the formula (A) given and defined in Claim or a salt thereof, whenever prepared by a process claimed in Claim 10.

12. A pharmaceutical composition according to Claim 5, substantially as hereinbefore described. For the ^Applicants