IE904447A1 - N-Heteroaralkyl-Substituted 1-Aryloxy-2-Propanolamine and¹Propylamine Derivatives Possessing Class III Antiarrhythmic¹Activity - Google Patents

Abstract

This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to methods for production thereof.

Description

N-HETEROARALKYL-SUBSTITUTEP 1-ARYLOXY-2-PROPANOLAMINE ANP PROPYLAMINE DERIVATIVES POSSESSING CLASS ΠΙANTIARRHYTHMIC ACTIVITY BACKGROUND QF THE INVENTION Class III antiarrhythmic agents may be categorized as having the ability to markedly prolong dog Purkinje fiber action potential duration without producing significant changes in maximal upstroke velocity. Unlike Class I anti-arrhythmic agents, a pure Class III agent displays no effect on cardiac sodium channels. The electrophysiologic properties of a compound defining a Class III activity profile are observed in vivo as negligible effects on atrial, ventricular and H-V conduction lines while producing a marked increase (greater than 20 percent) in both the atrial and ventricular refractory period. In contrast, Class I agents will demonstrate a marked slowing of ventricular conduction velocity, generally without significant changes in the refractory period. Recent reviews of these agents are by; Bexton et al., Pharmac. Ther., 17, 315-55 (1982); Vaughan-Williams, J. Clin. Pharmacol., 24, 129-47 (1984); and Steinberg et al., Ann. Rep. Med. Chem., 21. 95-108 (1986).

The following workers have reported the selective Class ΠΙ antiarrhythmic activity of the dextro enantiomer of 4-(2-isopropylamino-l-hydroxyethyl)-methanesulfonamide (MJ-1999, Sotalol): Taggart et al., Clin. Sci., 69. 631-636 (1985) and McComb et al., J.

Am. Coll. Cardiol., 5, 438 (1985).

Wohl et al., disclose N-[2-(diethylamino)ethyl]-4-[(methylsulfonyl)amino]-benzamide hydrochloride as a potential class III antiarrhythmic agent in US Patent 4,544,654, October 1, 1985.

Cross et al., have recently reported various N-heterocycle methyl substituted aphenylethylamine derivatives as useful antiarrhythmic agents in European Patent 0281254, September 7, 1988, as well as other alkyl-sulfonamide compounds reported in European Patent 0286277 and European Patent 0286278, October 12, 1988.

AHP-9521/C1 -2DESCRIPTIQN OF THE INVENTION In accordance with this invention, there is provided a group of antiarrhythmic agents classified by their pharmacological profile as Class III antiarrhythmic agents of the formula (I): R2 I wherein R1 is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 carbon atoms, perfluoroalkylsulfonamido of 1 to 6 carbon atoms, perfluoroalkylamido of 1 to 6 carbon atoms, alkylsulfone or alkylsulfoxide of 1 to 6 carbon atoms, NO2, CN, or 1imidazoyl; R2 is straight or branched alkyl chain of 1 to 6 carbon atoms ;X is O, S, or NR3 wherein R3 is H or a straight or branched alkyl chain of 1 to 6 carbon atoms; Y is CH2 or CHOH; Het is selected from the group consisting of R4 wherein R4 is H, -NHSO2 (Ci to Ce alkyl), -NHCO(Ci to C6 alkyl) or NO2; and Z is O, S, or NR5 wherein R5 is H, Ci to C6 alkyl or the alkylsulfonamido of 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof.

Examples of alkyl as a group or part of a group, e.g. alkylsulfonamido, are methyl, ethyl, propyl, isopropyl and butyl. Examples of perfluoroalkyl are CF3 , C2F5 AHP-9521/C1 -3and C3F7. Examples of aryl are phenyl, naphth-l-yl and naphth-2-yl. Preferred values for R1 are nitro and alkylsulfonamido such as methylsulfonamido. Preferably X is O. Preferred values of Het are Preferably R4 is hydrogen or alkylsulfonamido, e.g. methylsulfonamido.

A preferred aspect of the present invention are the compounds of formula (II) wherein R1 is NO2 or methylsulfonamido; Y is CH2 or CHOH; and Het is selected from 15 the group consisting of wherein R4 is H or methylsulfonamido and the pharmaceutically acceptable salts thereof.

A further preferred aspect of the present invention are the compounds AHP-9521/C1 -4IE 904447 N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide; N-[4-[3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methanesulfonamide; N-[4-[3-[methyl(2-quinoxalinylmethyl)amino]propoxy]phenyl]methanesulfonamide; l-[(lH-benzimidazol-2-ylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol; N-[4-[3-[(lH-benzimidazol-2-ylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide; l-[methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)-2-propanol; l-[(2-benzofuranylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol; N-[4-[3-[(2-benzofuranylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide; l-[(2-benzoxazolylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol; and the pharmaceutically acceptable salts thereof.

It is to be understood that the definition of the compounds of formula (I) and (II) encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity.

Optical isomers may be obtained in pure form by standard separation techniques.

For example, a racemic mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a resolving agent for example by salt formation or formation of a covalent bond. The resulting mixture of optically active diastereoisomers may be separated by standard techniques (e.g. crystallization or chromatography) and individual optically active diastereoisomers then treated to remove the resolving agent thereby releasing the single enantiomer of the compound of the AHP-9521/C1 -5invention. Chiral chromatography (using a chiral support, eluent or ion pairing agent) may also be used to separate enantiomeric mixtures directly.

Stereospecific synthesis using optically active starting materials and/or chiral 5 reagent catalyst and/or solvents may also be employed to prepare a particular enantiomer.

For example, where the compound of formula (I) is prepared by an addition process creating an optical center then carrying out the reaction using a chiral catalyst or reagent or in a chiral environment can give the product as a single enantiomer.

The pharmaceutically acceptable salts of the antiarrhythmic agents of this invention are prepared directly by neutralization of the free base. These physiologically acceptable salts may be formed with organic or inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, sulfamic, nitric, methylsulfonic, acetic, maleic, suc15 cinic, fumaric, tartaric, citric, salicylic, lactic, napthalenesulfonic acid and the like.

This invention also provides processes for preparing the compounds of formula (I). More particularly, the compounds of formula (I) may be prepared by one of the following processes: a) reacting a compound of formula wherein X and R1 are as defined above, with a compound of formula HN(R2)CH2Het (ΙΠ) wherein R2 and Het are as defined above to give a compound of formula (I) wherein Y is 30 CHOH; or b) reacting a compound of formula AHP-9521/C1 (IV) wherein R1 and X are as defined above, with a compound of formula (V) wherein R2 and Het are as defined above to give a compound of formula (I) wherein Y is CHOH; or c) reacting a compound of formula (VI) wherein R1 and X are as defined above and L is a leaving group, e.g. an aryl- or alkylsulphonyloxy group such as p-tolyl- or methane -sulphonyloxy, with a compound of formula (III) as defined above, to give a compound of formula (I) wherein Y is CH2; or d) of formula reacting a compound of formula (IV) as defined above with a compound (VII) wherein R2, Het and L are as defined above to give a compound of formula (I) wherein Y is CH2; or e) reacting a compound of formula IE 903647 AHP-9521/C1 NHR2 (VIII) R1 wherein R1, X and R2 are as defined above with A) a compound of formula 5 L-CH2-Het (IX) or B) a compound of formula O=CH-Het (X) wherein L and Het are as defined above, the reaction being carried out under reductive amination conditions when the compound of formula (X) is used, to give a compound of formula (I); or f) reducing a compound of formula COHet (Xi) R1 wherein X, Y, R1, R2 and Het are as defined above to give a compound of formula (I); or g) reductively aminating a compound of formula R1 Het (ΧΙΠ) AHP-9521/C1 IE 903647 -8wherein R1, X, Y and Het are as defined above, with an aldehyde of formula R3CHO wherein R3 represents hydrogen or alkyl of 1 to 5 carbon atoms; or h) acylating a compound of formula (I) wherein R1 is amino to give a corresponding compound of formula (I) wherein R1 is an alkyl-, aryl- or perfluoroalky 1-sulfonamido group or a perfluoroalkylamido group; or i) acidifying a compound of formula (I) to give an acid addition salt or neutralizing an acid addition salt of a compound of formula (I) to give the free base.

With regard to processes a) and b) the reaction may be conveniently carried out at room temperature or with heating in a polar inert solvent such as an alcohol, acetone or acetonitrile.

With regard to processes c), d) and e) A) the reaction may be carried out in the presence of a suitable base such as diisopropylamine, triethylamine or an alkali metal carbonate or bicarbonate in an inert polar solvent.

With regard to processes e) B) and g) the reductive amination may be effected using hydrogen in the presence of a suitable catalyst such as palladium on carbon or sodium cyanoborohydride according to standard procedures, e.g. using an alcohol solvent.

Process f) may be conveniently carried out using a reducing agent such as diborane or lithium aluminiumhydride in an inert solvent.

Process h) may be carried out under standard acylation procedures optionally in the presence of a base.

The compounds of this invention wherein Y is CHOH may be prepared by reaction of an appropriately substituted aryl epoxide with the required secondary amine in solvents such as acetone or acetonitrile: AHP-9521/C1 R2 / HN Het ch3cn 25 - 80 °C wherein R1, R2, Het and X are as defined above.

When Y is CH2, the compounds can be prepared by the reaction of an appropriately substituted alkyl halide with the required secondary amine in the presence of a suitable base in solvents such as acetone or acetonitrile: wherein R1, R2, Het and X are as defined above and W is chlorine or bromine.

These reactants are generally known compounds or otherwise are routinely prepared by techniques well within the skill of the chemist.

The compounds of this invention demonstrate antiarrhythmic activity when tested in the standard experimental animal in accordance with the following procedure.

Ventricular Fibrillation Threshold Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized with sodium pentobarbital (35 mg/kg i.v. supplemented with 5 mg/kg/h) and artificially ventilated with room air (minute volume: 200 mL/kg).

A right thoracotomy was performed at the fifth intercostal space and the heart suspended in a pericardial cradle. Bipolar electrodes for stimulation were sutured to the free wall of the right atrium and to the right ventricle.

IE 903647 AHP-9521/C1 - 10Arterial blood pressure and lead II ECG were displayed on a chart recorder and monitored on an oscilloscope. The dog heart was paced by a stimulus for driving a constant current isolation unit.

Ventricular fibrillation threshold (VFT) was determined during atrial pacing at 2.5 Hg. Trains of 4-msec duration square-wave pulses (50Hz, 200-msec duration) were delivered to the right ventricle via the epicardial bipolar electrode (silver contacts 1 mm in diameter and 5 mm apart embedded in acrylic matrix). Trains of pulses were delivered every 12th paced beat and were timed to terminate with the end of the T wave of the ECG. Current intensity was increased progressively until ventricular fibrillation (VF) occurred. The lowest current intensity producing VF was defined as the ventricular fibrillation threshold (VFT). When fibrillation occurred the heart was defibrillated within 10 seconds from the onset of fibrillation using a defibrillator charged to 10 J. After defibrillation the animal was allowed to recover for at least 30 minutes or until the ECG returned to normal. VFT was measured twice before drug administration to establish a stable pre-drug threshold.

Dogs were randomized to receive either test drug or vehicle by i.v. route. Animals treated with vehicle do not show any significant increase of VFT. The ability of test agents to elevate the threshold generally is accepted as an indication of potential antifibrillary activity, as vehicle-treated animals on repeated trials do not show any appreciable increase of VFT. This conclusion is supported by the observation that a substantial fraction of the animals treated with the test drug spontaneously defibrillate and return to sinus rhythm. Spontaneously defibrillation of vehicle treated animals is an exceedingly rare phenomenon.

Ventricular Fibrillation Threshold in Dog (n=6; x + S.E.) Pre-Drug Vehicle Cmpd 4 (5 mg/kg) + 2* * 25 + 7 * * Current threshold in mA necessary to induce fibrillation. • 2 to the 6 animals defibrillated spontaneously AHP-9521/C1 -11 IE 903647 Cardiac Electrophysiology The compounds of this invention display a Class III antiarrhythmic profile. The Class ΠΙ antiarrhythmic activity was established in vitro and in vivo in accordance with the following standard test procedures: In Vitro Bundles of free-running Purkinje fibers with attached myocardium obtained from either ventricle of adult dog heart were pinned without stretching to the bottom of a 10 mL tissue chamber and continuously superfused with oxygenated Tyrode's solution at a flow rate of 5 mL/minute. The composition of the Tyrode's solution was (mM): NaCl, 138; KCl 4; CaCl2, 2; MgCl2, 0.5; NaHCO3, 24; dextrose, 5.5. The solution was aerated with 95% 02-5% CO2 at 37°C. Bath temperature was maintained at 37±0.5°C. by circulating the pre-warmed superfusate through a thermostatically controlled water bath immediately prior to entering the tissue chamber.

The preparations were stimulated through bipolar Teflon-coated silver wires, bared at the tips, placed on the endocardial surface of the attached myocardium, using a digital stimulator set to deliver constant current pulses 1.5-msec in duration at cycle lengths of 300 or 1000 msec. Stimulus strength was set at approximately 2 x diastolic threshold, and adjusted as required throughout the experiment. All preparations were allowed to equilibrate in the tissue chamber for at least 1 hour before measurements were begun. Subsequently, a minimum of 60 minutes were allowed for equilibration with each drug-containing superfusate before post-drug measurements were made. Impalements were made at 6 to 10 sites throughout the preparation before and after drug exposure. Offset potentials were rechecked after each impalement.

Glass microelectrodes filled with 3M KCl were coupled to high impedance negative capacitance electrometers and Ag/AgCl half-cells used as reference electrodes. The first derivative of the action potential upstroke (Vmax) was obtained using an analog differentiator circuit, coupled to a peak-hold circuit that retained the recorded value of Vmax for 30 to 70-msec. Action potential and Vmax tracings were displayed on a storage oscilloscope, and photographed for later analysis. In addition, chart paper recordings of Vmax were obtained using the peak-hold device output.

AHP-9521/C1 - 12Fresh stock solutions of drug were prepared for each experiment. Compounds were dissolved in distilled water at total concentrations of 1 to 10 mg/mL, and subsequently diluted to a final concentration of 3 to 10 μΜ in appropriate volumes of normal Tyrode's solution for evaluation.

Action potential (AP) parameters measured included: diastolic take-off potential (or activation voltage, V(act); AP overshoot (Vos); AP duration measured as the time taken to repolarize to -20 mV (APD-20), -60 mV (APD.go), and -80 mV (APD.so); and maximal upstroke velocity (Vmax). An increase in APD_60 that occurred without a significant change in Vmax was taken, by definition, to indicate Class III antiarrhythmic activity in vitro.

In Vivo Mongrel dogs of both sexes weighing 12 to 18 kg were anesthetized with sodium pentobarbital (35 mg/kg i.v. supplemented with 5 mg/kg/h) and artificially ventilated with room air (minute volume: 200 mL/kg).

The heart was exposed by a right thoractomy performed at the fifth intercostal space and suspended in a pericardial cradle. Epicardial electrodes for stimulation and recording were sutured to the free wall of the lower right atrium and near the base of the right ventricle. Each electrode set contained a linear array of electrodes consisting of 1 bipolar stimulating electrode and 2 bipolar recording electrodes embedded in a rigid acrylic matrix. The stimulating bipole was 7 mm from the proximal recording electrode, which in turn was 10 mm from the distal recording bipole. Each electrode array was oriented to be parallel to the epicardial fiber axis.

Arterial blood pressure and lead II ECG were displayed on a chart recorder and monitored on an oscilloscope. Conduction times and refractory periods were measured during pacing at a cycle length of 300 msec. The dog heart was paced by a stimulator driving a constant current isolation unit. Electrical signals from the atrial and ventricular electrodes were displayed on a digital oscilloscope and recorded by a ink-jet recorder. Diastolic threshold was determined before and after each trial. - 13ΑΗΡ-952 I/O Refractory periods of the right atrium and right ventricle (AERP and VERP) were 5 determined by introducing an extrastimulus (S2) every 8 paced beats (Si). The extrastimulus was followed by a 4-second rest interval during which no pacing occurred. Both Si and S2 were of identical intensity (twice threshold) and duration (2 msec). The S1-S2 interval was gradually decreased in 2-msec steps until the extra-stimulus failed to induce a propagated response. This S1-S2 interval was considered to define effective refractory period.

Atrial and ventricular (ACT and VCT) conduction times were measured as the time interval between the 2 electrograms recorded at the proximal and distal sites of the recording electrode array. The time of activation for electrograms with predominantly biphasic complexes was taken as the moment when the trace crossed the zero reference line, and for triphasic complexes, as the peak of the major deflection.

Animals received the test compound by i.v. injection. Drugs were administered cumulatively at the following dose levels: 1, 2.5, 5, 7.5, 10 mg/kg. Each dose was administered over a 3 minute period. Electrophysiologic testing was performed 15 minutes following the end of dosing. Every 30 minutes the dog received the next incremental dose.

Vehicle-treated animals did not show any significant change of the 25 electrophysiologic parameters. An increase in ERP that occurred without a significant decrease of CT was taken, by definition to indicate in vivo Class III antiarrhythmic activity.

AHP-9521/C1 - 145 The results of the assays are set forth in the table below: Biological Data Example Purkinje riber 3μΜ Anesthetized Dog (5 mg/kg) BCL = 300 BCL = 1000 BCL = 300 APD-60 Vmax APD.60 Vmax AERP VERP ACT VCT HR BP 1 71 1* 71 17 -4 -3 -24 -22 2Ψ 61 7 38 9 41 18 26 -6 -20 -22 3 (did not pace) 129 8 90 14 -5 -8 -25 -13 7 18 2 32 15 6 17 2 43 1 36 11 -8 -6 8 -8 5 8 12 26 26 25 13 -7 0 -23 8 4 27±4 (n = 3) -9±3 62±10 -7±6 51 (n = 2) 27 -11 0 (n = 2) -22 -17 8 22 +3 (n=2) 45 5 52 30 (n=2) -6 1 -21 -8 9 27 -1 43 -4 * Paced at 500 msec Ψ Dosed at 10 mg/kg in anesthetized dog and at 10 μΜ in Purkinje fiber Based upon the activity profile elicited by the compounds of this invention in the above-described standard scientifically recognized test models, the compounds are established as antiarrhythmic agents useful in the treatment of cardiac arrhythmia and conditions characterized by coronary arteries vasospasm. For that purpose, the compounds may be administered orally or parenterally in suitable dosage forms compatible with the route of administration, whether oral, intraperitoneal, intramuscular, intravenous, internasal, buccal, etc. The effective dose range determined in the animal test models has been established at from about 1 to about 5 milligrams per kilogram host body weight (preferably from 2 to 10 mg/kg) i.v., and from about 2 to about 10 mg/kg (preferably 5 to 20 mg/kg) p.o., to be administered in single or plural doses as needed to relieve the AHP-9521/C1 - 15arrhythmatic dysfunction. The specific dosage regimen for a given patient will depend upon age, pathological state, severity of dysfunction, size of the patient, etc. Oral administration is performed with either a liquid or solid dosage unit in any conventional form such as tablets, capsules, solutions, etc., which comprise a unit dose (e.g. from about 50 milligrams to about 400 milligrams) of the active ingredient alone or in combination with adjuvants needed for conventional coating, tableting, solubilizing, flavoring or coloring. Parenteral administration with liquid unit dosage forms may be via sterile solutions or suspensions in aqueous or oleaginous medium. Isotonic aqueous vehicle for injection is preferred with or without stabilizers, preservatives and emulsifiers.

Accordingly, this invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The following examples illustrate the preparation of a representative number of compounds of this invention.

EXAMEEE-1 l-r(lH-Benzimidazol-2-vlmethvl)methvlaminol-3-(4-nitrophenoxv)2-prppanpl Step 1) Preparation of l-p-Nitrophenoxy-2,3-propene To a solution of p-nitro sodiumphenoxide (30 g, 0.186 mol) in DMF (400 mL) was added allyl bromide (24 mL, 0.28 mol). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 48 hours, then diluted with water (300 mL) and extracted with ether (3 x 100 mL). The combined organic fraction was diluted with pentane until it became turbid. It was then washed with water (2 x 100 mL), dried (MgSC>4), and concentrated to afford 27.5 g of product (83%) as a red oil of sufficient purity to use in the next step.

*H NMR (CDC13): δ 8.19 (d, 2H, J=8 Hz, ArH), 6.97 (d, 2H, J=8 Hz, ArH), 6.17 (m, 1H, -CH=CH2), 5.40 (m, 2H, -CH=CH2), 4.65 (d, 2H, J=6 Hz, O-CH2-).

AHP-9521/C1 - 16Step 2) Preparation of l,2-Epoxy-3-(p-nitrophenoxy)propene To a solution of l-p-nitrophenoxy-2,3-propene (19.25 g, 0.107 mol) in dry 5 methylene chloride (300 mL) was slowly added meta-chloroperbenzoic acid (24.13 g, 0.14 mol). The reaction mixture was stirred under a nitrogen atmosphere for 48 hours. The mixture was filtered and the filtrate was concentrated to afford a yellow residue. Trituration of the yellow residue with ether yielded the crude product as yellow crystals. Purification by flash chromatography afforded 11.75 g (56%) of product as a light yellow solid m.p. 63-65’C. !Η NMR (CDC13): δ 8.15 (d, J=8.2 Hz, 2 ArH), 6.95 (d,J=8.2 Hz, 2 ArH), 4.36 and 3.98 (2m, -OCH9-CH). 3.36 (m, 1H, epoxide methine), 2.92 and 2.76 (2m, 2H, epoxide methylene) Anal. Calcd.: C, 59.19; H, 5.87; N, 6.27 Found: C, 59.51; H, 5.84; N, 6.31.

Step 3) Preparation of 2-(Methylaminomethyl)benzimidazole 2-Chloromethylbenzimidazole (3.00 g, 18.01 mmol) was dissolved in aqueous methylamine (50 mL, 40 wt % in H2O) at 10°C under N2. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 4 hours. Water was added and the mixture extracted with methylene chloride. The organic phase was dried (MgSC>4) and concentrated to afford crude product which was purified by HPLC (gradient methanol/methylene chloride) to afford 0.650 g (22%) of pure product as a tan solid.

JH NMR (CDCI3): δ 7.56 (m, 2H, ArH), 7.22 (m, 2H, ArH), 4.07 (s, 3H, CH2NHCH3), 2.51 (s, 3H, NHCH3).

Step 4) Preparation of l-[(lH-Benzimidazol-2-ylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol AHP-9521/C1 -172-(Methylaminomethyl)benzimidazole (0.459 g, 3.07 mmol) was added to a solution of l,2-epoxy-3-(p-nitrophenoxy)propane (0.600 g, 3.07 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated in vacuo. The residue was purified by chromatotron (10% MeOH/CH2Cl2), then treated with ethanolic HCl and ether to afford 0.450 g (34%) of the title compound as a pale yellow solid dihydrochloride salt m.p. 207-209°C. Ή NMR (DMSO-d6): δ 8.20 (d, J=9.22 Hz, 2H, ArH), 7.73 (m, 2H, ArH), 7.39 (m, 2H, ArH), 7.13 (d, J=9.32 Hz, 2H, ArH), 4.74 (s, 2H, C-CH2-N-CH3), 4.45 (br m, 1H, CHOH), 4.15 (m, 2H, OCH2), 3.43 and 3.37 (m, 2H, -CHOHCH2-N-), 2.95 (s, 3H, NCH3) IR (KBr, cm-1): 3280 (NH®), 1500 (C=N) MS (m/e): 357 (MH+, 94%), 133 (100%) Anal Calcd: C, 50.35; H, 5.16; N, 13.05 Found: C, 50.09; H, 5.02; N, 13.04.

EXAMPLE 2 N-i4-i3-f(lH-Benzimidazol-2-vlmethvl)methvlamino1-2-hYdroxYr propoxvlphenvlmethanesulfonamide Step 1) Preparation of 3-[(4-Amino)phenoxy]-l-propene To 3-[(4-nitro)phenoxy]-l-propene, prepared by the process of Example 1, Step 1, (12.65 g, 70.67 mmol) in concentrated HCl (85 mL) at 0°C, was slowly added stannous chloride (48 g, 212 mmol). After stirring for 20 minutes at 55’C, the mixture was cooled to O’C and carefully basified with 50% NaOH. The cloudy mixture was extracted with ether. The organic phase was decolorized (charcoal), dried (MgSO4), and concentrated to afford product (8.50 g, 81%) as a yellow oil which was used directly in the next step.

AHP-9521/C1 - 18JH NMR (CDCI3): δ 7.05 (m, 4H, ArH), 6.4 (m, 1H, OCH2-CH=CH2), 5.70 (m, 2H, CH2CH=CH2), 4.80 (d, 2H, OCH2CH=CH2).

Step 2) Preparation of N-[4-(2-Propenoxy)phenyl]methanesulfonamide Methanesulfonyl chloride (5.06 mL, 65.32 mmol) was added to a stirred solution of 3-[(4-amino)phenoxy]-l-propene (8.11 g, 54.43 mmol) in pyridine (80 mL) at 0°C. The mixture was stirred for 72 hours and was then poured slowly into ice-water and extracted with ether. The organic phase was washed with cold IN HCl and was then extracted with IN NaOH solution. The aqueous phase was acidified and the product (9.05 g, 73%) precipitated out as a white solid.

!H NMR (CDCI3): δ 7.18 (d, J=6.75 Hz, 2H ArH), 6.88 (d, J=8.94 Hz, 2H ArH), 6.00 (m, 1H, CH2CH=CH2), 5.40 and 5.30 (2m, OCH=CH2), 4.50 (m, OCH2CH=CH2) Anal. Calcd.: C, 52.85; H, 5.76; N, 6.16 Found: C, 52.80; H, 5.63; N, 5.99.

Step 3) Preparation of l-[(4-Methanesulfonamido)phenoxy]-2,3-propeneoxide m-Chloroperoxybenzoic acid (12.16 g, 70.48 mmol) was added to a solution of N[4-(2-propeneoxy)phenyl]methanesulfonamide (8.00 g, 35.24 mmol) in methylene chlo25 ride (120 mL). The mixture was stirred overnight at reflux, cooled, and filtered.

Concentration afforded crude product which was purified by flash chromatography using 1:1 hexane/ethyl acetate. Yield 5.55 g (65%) of white solid. >H NMR (CDCI3): δ 7.17 (d, J=6.87 Hz, 2H ArH), 6.90 (d, J=8.93 Hz, 2H, ArH), 6.40 (br s, NHSO2CH3), 4.20 (dd, Ji=5.54 Hz, J2=2.98 Hz, 1H, epoxide Cfh), 3.90 (dd, H 1=5.54, J2=5.78 Hz, 1H, epoxide Cih), 3.35 (m, 1H, epoxide CH), 2.94 (s, 3H, NHSO2CH3), 2.90 and 2.76 (2m, OCH2) |Ε 904447 AHP-9521/C1 - 19IR (KBr): 3240 (NH) MS (m/z): 243 (60% M+), 164 (100%) Anal. Calcd.: C, 49.37; H, 5.39; N, 5.76 Found: C, 49.69; H, 5.63; N, 5.63.

Step 4) N-[4-[3-[(lH-Benzimidazol-2-ylmethyl)methylamino]-2-hydroxypropoxy] phenyl] methanesulfonamide 2-(Methylaminomethyl)benzimidazole, prepared by the procedure of Example 1, Step 3, (0.993 g, 6.16 mmol) was added to a solution of l,2-epoxy-3-(p-methanesulfon15 amidophenoxy)propane (1.5 g, 6.16 mmol) in acetonitrile (12 mL). The reaction mixture was stirred at reflux for 18 hours, cooled to 0°C and vacuum filtered. The solids were washed with cold ether and dried under heated vacuum to afford 1.32 g (53%) of analytically pure product m.p. 163-165*C.

*H NMR (DMSO-d6): δ 9.33 (br s, 1H, NHSO2CH3), 7.52 and 7.44 (m, 2H, ArH), 7.10 (d, J=9.02 Hz, 2H, ArH), 7.09 (m, 2H, ArH), 6.98 (d, J=8.96 Hz, 2H, ArH), 4.93 (br s, 1H, OH), 3.95 (m, 2H, OCH2), 3.79 (s and m, 3H, CH3NCH2 and CHOH), 2.86 (s, 3H, NHSO2CH3), 2.59 and 2.51 (m, 2H, CHOHCH2NCH3), 2.27 (s, 3H, NCH3) IR (KBr, cm-1): 3290 (NH) MS (m/e): 405 (MH+, 18%), 131 (100%) Anal Calcd: C, 56.42; H, 5.98; N, 13.85 Found: C, 56.24; H, 5.94; N, 13.81.

EXAMPLE 3 l-iMethvl(2-auinolinvlmethvnaminol-3-(4-nitroDhenoxv)2-propanol AHP-9521/C1 -20Step 1) Preparation of 2-(Methylaminomethyl)quinoline 2-Chloromethylquinoline hydrochloride (3.00 g, 14.01 mmol) was suspended in 5 aqueous methylamine (40 mL, 40 wt % in H2O) at 10°C under a N2 atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with water and extracted with methylene chloride. The organic extracts were dried (MgSCM) and concentrated to afford 2.22 g (92%) of pure product as a brown oil. lH NMR (CDC13): δ 8.08 (m, 2H, ArH), 7.78 (d, J=8.11 Hz, 1H, quinoline H4), 7.69 (m, 1H, ArH), 7.52 (d, J=7.03 Hz, 1H, ArH), 7.44 (d, J=8.72 Hz, 1H, quinoline H3), 4.06 (s, 2H, CH2NHCH3), 2.55 (s, 3H, NHCH3).

Step 2) Preparation of l-[Methyl(2-quinolinylmethyl)amino]-3-(4-nitrophenoxy)2-propanol 2-(Methylaminomethyl)quinoline (1.76 g, 10.22 mmol) was added to a solution of 20 l,2-epoxy-3-(p-nitrophenoxy)propane, prepared by the procedure of Example 1, Step 2, (1.00 g, 5.12 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated in vacuo. The residue was purified by flash column chromatography (3% MeOH - CH2C12) and then treated with ethanolic HCl and ether to afford 0.510 g (13%) of title compound as the white solid dihydrochloride salt m.p. 154-157°C. lH NMR (DMSO-d6): δ 10.27 (br s, 1H, NH®), 8.50 (d, J=8.43 Hz, 1H, quinoline H), 8.17 (d, J=9.28 Hz, 2H, ArH), 8.03 (tr, J=6.89 Hz, 2H, ArH), 7.82 (m, 1H, ArH), 7.72 (d, J=8.46 Hz, 1H, quinoline H), 7.67 (m, 1H, ArH), 7.07 (d, J=9.26 Hz, 2H, ArH), 4.78 (s, 2H, C-CH2NCH3), 4.50 (br m, 1H, CHOH), 4.12 (d, J=5.04 Hz, 2H, OCH2), 3.50 and 3.36 (m, 2H, CHOH-Cih-N), 3.01 (s, 3H, NCH3) IR (KBr, cm-l): 3260 (NH+) AHP-9521/C1 -21 MS (m/e): 368 (MH+) Anal. Calcd: C, 54.56; H, 5.27; N, 9.54 Found: C, 55.00; H, 5.58; N, 9.16.

EXAMPLES N-r4-i3-i(2-Ouinolinvlmethvl)methvlaininol-2-hvdroxvpropoxvlptenyilmfithangsulfonamidg 2-(Methylaminomethyl)quinoline prepared by the procedure of Example 3, Step 1, (1.69 g, 9.86 mmol) in acetonitrile (4 mL) was added to a stirring solution of 1,2epoxy-3-(p-methanesulfonamidophenoxy)propane, prepared by the procedure of Example 2, Step 3, (2.00 g, 8.22 mmol) in acetonitrile (12 mL). The reaction mixture was heated at reflux for 18 hours, cooled and concentrated in vacuo. The residue was purified by flash column chromatography (10% MeOH-CH2Cl2) and then triturated with ethyl acetate/ether, filtered and dried under heated vacuum to afford 1.52 g (44%) of analytically pure product m.p. 118-120°C as a tan solid.

*H NMR (DMSO-d6): δ 9.34 (s, 1H, NHSO2CH3), 8.24 (d, J=8.48 Hz, 1H, quinoline H), 7.94 (m, 2H, ArH), 7.72 (m, 1H, ArH), 7.61 (d, J=8.52 Hz, 1H, quinoline H), 7.56 (m, 1H, ArH), 7.11 (d, J=9.01 Hz, 2H, ArH), 6.84 (d, J=8.93 Hz, 2H, ArH), 5.00 (br d, 1H, OH), 3.96 (m, 2H, OCH2), 3.82 (m, 3H, CCH2NCH3 + CHOH), 2.87 (s, 3H, NHSO2CH3), 2.61 and 2.49 (CHOHCH2NCH3), 2.28 (s, 3H, NCH3) IR (KBr, cm 1): 3450 (OH), 3180 (NH) MS (m/e): 416(MH+,60%) Anal Calcd: C, 60.70; H, 6.06; N, 10.11 Found: C, 60.60; H, 6.08; N, 9.85.

AHP-9521/C1 -22LX AMPLE 5 l-i(2-Benzoxazolvlmethvnmethvlaniinol-3-(4-iiitroDhenoxv)5 2-propanol Step 1) Preparation of 2-(Chloromethyl)benzoxazole A mixture of o-aminophenol (4.00 g, 36.6 mmol) and ethyl chloroacetimidate hydrochloride (8.68 g, 54.98 mmol) in ethanol (55 mL) was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and vacuum filtered. The filtrate was concentrated in vacuo, diluted with methylene chloride and filtered again. The methylene chloride filtrate was dried (MgSO4) and concentrated to afford 3.99 g (65%) of product as a brown oil which was used directly in the next step.

NMR (CDC13): δ 7.73 (m, 1H, ArH), 7.56 (m, 1H, ArH), 7.38 (m, 2H, ArH), 4.76 (s, 2H, CH2CI).

Step 2) Preparation of 2-(Methylaminomethyl)benzoxazole 2-(Chloromethyl)benzoxazole (3.99 g, 23.8 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10 °C under a nitrogen atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour.

The mixture was diluted with water and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (5% MeOH/CH2Cl2) to afford 3.18 g (82%) of pure product as a yellow oil.

!H NMR (CDCI3): δ 7.72 (m, 1H, ArH), 7.54 (m, 1H, ArH), 7.33 (m, 2H, ArH) 4.08 (s, 2H, CH2NHCH3), 2.56 (CH2NHCH3).

AHP-9521/C1 -23Step 3) Preparation of l-[(2-Benzoxazolylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol 2-(Methylaminomethyl)benzoxazole (1.86 g, 11.53 mmol) was added to a solution of l,2-epoxy-3-(p-nitrophenoxy)propane, prepared by the process of Example 1, Step 2, (1.5 g, 7.68 mmol) in acetonitrile (25 mL). The reaction mixture was heated at reflux for 24 hours and then stirred at room temperature for an additional 24 hours. The mixture was concentrated in vacuo. The residue was purified by chromatotron (10% MeOHCH2CI2) then treated with ethanolic HCl and ether to afford 2.12 g (70%) of pure title compound as the off-white solid hydrochloride salt m.p. 214-216°C. 1H NMR (DMSO-d^): δ 8.20 (d, J=9.13 Hz, 2H ArH), 7.84 (dd, Ji=7.67 Hz, J2=.415 Hz, 1H, ArH), 7.80 (dd, Ji=8.5O Hz, J2=l .25 Hz, 1H, ArH), 7.50 (m, 1H, ArH), 7.45 (m, 1H, ArH), 7.14 (d, J=9.33 Hz, 2H, ArH), 4.87 (s, 2H, C-CH2NCH3), 4.50 (br m, 1H, CHOH), 4.15 (d, J=4.77 Hz, 2H, OCH2), 3.54 (m, 2H, CHOH-CH2N), 3.05 (s, 3H, NCH3) IR (KBr, cm-1): 3160 (OH + NH®) MS (m/e): 358 (MH+) Anal Calcd: C, 54.90; H, 5.12; N, 10.67 Found: C, 55.35; H, 5.11; N, 10.68.

AHP-9521/C1 -24EXAMPLE6 N-i4-r3-r(2-Benzofuranvlmethyl)methvlaminol-2-hvdroxvpropoxvlphenvllmethanesulfonamide Step 1) Preparation of Benzofuran-2-methanol Molar diborane in tetrahydrofuran (61.6 mL, 61.6 mmol) was added dropwise over 10 minutes to a stirred solution of benzofuran-2-carboxylic acid (5.00 g, 30.8 mmol) in tetrahydrofuran (50 mL) at 0°C. Stirring was continued at 0°C for 30 minutes, then at room temperature for 18 hours. The reaction mixture was quenched carefully by slow addition of 1:1 THF/H2O, and extracted with ether. The organic extracts were dried (MgSO4) and concentrated to afford 3.58 g (78%) of product as a colorless oil.

*H NMR (DMSO-d6): δ 7.57 (m, 2H, ArH), 7.27 (m, 2H, ArH), 6.75 (s, 1H, CH=C-), 4.58 (s, 2H, CH2OH).

Step 2) Preparation of 2-(Chloromethyl)benzofuran Thionyl chloride (5.14 mL, 70.46 mmol) was added dropwise to a solution of benzofuran-2-methanol (3.58 g, 23.48 mmol) and pyridine (10 drops) in methylene chloride (60 mL). Stirring was continued at room temperature for 18 hours. The mixture was carefully diluted with water and extracted with methylene chloride. The organic extracts were washed with aqueous sodium bicarbonate, dried (MgSCU) and concentrated to afford crude product which was purified by flash column chromatography (10% EtOAc/hexanes) to afford 2.77 g (69%) of pure product as a yellow oil. 1H NMR (CDCI3): δ 7.52 (m, 2H, ArH), 7.27 (m, 2H, ArH), 6.73 (s, 1H, CH=C-), 4.69 (s, 2H, CifcCl).

Step 3) Preparation of 2-(Methylaminomethyl)benzofuran AHP-9521/C1 -252-(Chloromethyl) benzofuran (2.77 g, 16.63 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10°C under a nitrogen atmosphere. After 10 minutes, the reaction mixture was wanned to room temperature and stirring was continued for 72 hours. The mixture was diluted with water and extracted with methylene chlo5 ride. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (10% MeOH/CH2Cl2) to afford 1.00 g (37%) of pure product as a pale yellow oil.

!H NMR (CDCI3): δ 7.48 (m, 2H, ArH), 7.21 (m, 2H, ArH), 6.56 (s, 1H, CH=C-), 3.89 (s, 2H, CH2NHCH3), 2.47 (s, 3H, NHCH3).

Step 4) Preparation of N-[4-[3-[(2-Benzofuranylmethyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide 2-(Methylaminomethyl)benzofuran (0.927 g, 6.16 mmol) was added to a solution of l,2-epoxy-3-(p-methanesulfonamidophenoxy)propane (1.4 g, 6.16 mmol) in acetonitrile (12 mL). The reaction mixture was heated at reflux for 48 hours, cooled and concentrated in vacuo. The residue was purified by chromatotron (10% MeOH/CH2Cl2) twice to afford an oil which was treated with ethanolic HCl and ether to give 0.640 g (25%) of pure product as the white solid hydrochloride salt m.p. 182-183°C.

!H NMR (DMSO-d6): δ 9.14 (s, 1H, NHSO2CH3), 7.72 (d, J=7.68 Hz, 1H, ArH), 7.61 (d, J=6.39 Hz, 1H, ArH), 7.39 (m, 1H, ArH), 7.30 (tr, J=7.34 Hz, 7.25 Hz, ArH), 7.23 (s, 1H, CH=C-), 7.13 (d, J=8.85 Hz, 2H, ArH), 6.88 (d, J=8.93 Hz, 2H, ArH), 6.02 (br m, 1H, OH), 4.65 (br s, 2H, -C-CH2NCH3), 4.41 and 4.29 (br m, 1H, CHOH), 3.91 (d, J=4.98 Hz, 2H, OCH2), 3.34 (s, 3H, NHSO2CH3), 3.26 (m, 2H, CHOH-CH2N), 2.87 (s, 3H, NCH3) IR (KBr, cm'1): 3320 (NH) MS (m/e): 404 (M+), 131 (100%) Anal Calcd: C, 54.48; H, 5.71; N, 6.35 Found: C, 54.43; H, 5.64; N, 6.15.

AHP-9521/C1 -26EXAMPLE7 l-i(2-Benzofuranvlmethyl)methvlaminol-3-(4-nitrophenoxv)2-propanol 2-(Methylaminomethyl)benzofuran, prepared by the process of Example 6, Step 3, (0.991 g, 6.14 mmol) was added to a solution of l,2-epoxy-3-(p-nitrophenoxy)propane, prepared by the process of Example 1, Step 2, (0.600 g, 3.07 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated in vacuo. The residue was purified by flash column chromatography (5% MeOH/CH2Cl2), then treated with ethanolic HCl and ether to afford 0.8 g (66%) of the hydrochloride salt of the title compound as a pale yellow solid m.p. 208-209°C. 1H NMR (DMSO-d6): δ 10.44 (br s, 1H, NH®), 8.20 (d, J=9.28 Hz, 2H, ArH), 7.72 (d, J=7.63 Hz, 1H ArH), 7.61 (d, J=8.28 Hz, 1H, ArH), 7.39 (m, 1H, ArH), 7.30 (m, 1H, ArH), 7.25 (s, 1H, CH=C-), 7.12 (d, J=9.24 Hz, 2H, ArH), 6.12 (br s, 1H, OH), 4.65 (s, 2H, C-CH2NCH3), 4.49 and 4.37 (brm, 1H, CHOH), 4.13 (d, J=3.86 Hz, 2H, OCH2), 3.39 and 3.29 (m, 2H, CHOH-CH2-N-), 2.87 (s, 3H, NCH3) IR (KBr, cm'1): 3220 (NH®) MS (m/e): 356 (M+), 131 (100%) Anal Calcd: C, 58.09; H, 5.39; N, 7.13 Found: C, 58.00; H, 5.61; N, 6.92.

EXAMPLE 8 N-i4-f3-iMethvl(2-auinolinvlmethvl)aminolpropoxvlphenvllniethanesulfonamide Step 1) Preparation of 2-[N-[3-(4-Nitrophenoxy)propyl]methylaminomethyl]quinoline AHP-9521/C1 -27To a stirred suspension of 2-(methylaminomethyl)quinoline, prepared by the procedure of Example 3, Step 1, (3.67 g, 21.35 mmol), sodium iodide (2.78 g, 18.56 mmol), and potassium carbonate (3.08 g, 138.21 mmol) in acetonitrile (80 mL) was added 3chloropropyl-4-nitrophenyl ether (4.00 g, 18.56 mmol). The mixture was stirred at 80°C overnight, concentrated and partitioned between 10% K2CO3 and ethyl acetate. The organic phase was washed with brine, dried (MgSC>4), and concentrated to afford an oil. The product was purified by HPLC (10% MeOH/CH2Cl2) to afford 2.34 g (36%) of pure product as a yellow oil.

!H NMR (CDCI3): δ 8.2-7.9 (m, 4H, quinoline H), 7.7 (m, 2H, quinoline H), 7.5 (d, J=6 Hz, 2H, ArH), 6.8 (d, J=6.2 Hz, 2H, ArH), 4.1 (t, J=4.8 Hz, 2H, -OCH2), 3.8 (s, 2H, -NCH2), 2.62 (t, J=4 Hz, -CH2N-), 2.35 (s, 3H, NCH3), 2.0 (m, 2H, -CH2CH2CH2-).

Step 2) Preparation of 2-[N-[3-(4-Aminophenoxy)propyl]methylaminomethyl]quinoline A mixture of N-[(4-nitrophenoxy)propoxy[methyl]]aminomethylquinoline (1.97 g, 5.61 mmol) and 5% Pd/C (0.197 g) in ethyl acetate (40 mL) in a Parr reactor was charged with 50 PSI H2 and left overnight. The mixture was then filtered through solka floe and concentrated to afford 1.86 g (100%) of amine as a yellow oil which was used directly in the next step.

]H NMR (CDCI3): δ 8.1 (m, 2H, quinoline H), 7.8-7.4 (m, 4H, quinoline H), 6.70 (br q, 4H, ArH), 3.95 (t, J=4.8 Hz, -OCH2-), 3.84 (s, 2H, N-CH2-), 3.38 (br s, 2H, -NH2), 2.64 (t, J=4.8 Hz, -CH2-N-), 2.31 (s, 3H, -NCH3), 1.97 (m, 2H, -CH2-CH2-CH2-).

Step 3) Preparation of N-[4-[3-[Methyl(2-quinolinylmethyl)amino]propoxy]30 phenyl] methanesulfonamide Methanesulfonylchloride (0.52 mL, 6.73 mmol) was added dropwise to a stirred solution of N-[(4-aminophenoxy)propoxy[methyl]]aminomethylquinoline (1.80 g, 5.61 mmol) in pyridine (20 mL) at O’C. The resulting mixture was stirred at room temperature AHP-9521/C1 -28ovemight. The reaction was quenched with ice chips and extracted with ethyl acetate. The organic phase was dried (MgSCM), decolorized (charcoal), and concentrated to afford crude product which was purified by chromatotron (5% CH3OH/CH2CI2) to yield 0.88 g of an oil which was triturated with ether/hexane to form a white solid m.p. 83-86°C.

NMR (CDCI3): δ 8.06 (m, 2H, quinoline H), 7.8 (d, J=8.1 Hz, 1H, quinoline H), 7.7 (m, 1H, quinoline H), 7.58 (d, J=8.47 Hz, 1H, quinoline H), 7.52 (m, 1H, quinoline H), 7.15 (d, J=8.85 Hz, 2H, ArH), 6.81 (d, J=8.88 Hz, 2H, ArH), 4.02 (t, J=6.26 Hz, 2H, -OCH2), 3.86 (s, 2H, NCH2-), 2.95 (s, 3H -SO2CH3), 2.66 (t, J=6.93 Hz, -CH2N-), 2.34 (s, 3H, NCH3), 2.01 (m, 2H, -CH2CH2CH2-) IR (KBr, cm'1): 2900 (NH) MS (m/e): 400 (MH+, 100%), 259, 144 Anal. Calcd: C, 63.13; H, 6.31; N, 10.52 Found: C, 62.86; H, 6.23; N, 10.30.

EXAMPLE 9 N-r4-r3-fMethvl(2-QuinoxaIinvlmethvl)aminolpropoxvlphenvllmethanesulfonamide Step 1) Preparation of 2-(Bromomethyl)quinoxaline To a stirring solution of 2-methylquinoxaline (20.0 g, 155 mmol) and benzoyl 25 peroxide (3 g, 12 mmol) in carbon tetrachloride (800 mL) was added l,3-dibromo-5,5dimethyl hydantoin (22 g, 77 mmol). The resulting mixture was irradiated with a spotlight (200 watt) for 1.5 hours. The mixture was cooled, filtered, and concentrated to afford crude product which was purified by HPLC (4:1 hexane/EtOAc) to yield 14.0 g (40%) of monobromomethyl product as a grey solid: lH NMR (CDCI3): δ 9.00 (s, 1 H, ArH), 8.10 (m, 2 H, ArH), 7.80 (m, 2 H, ArH), 4.72 (s, 2 H, Br£H2-Ar); and 15.0 g (35%) of dibromomethyl product as a white solid: lH NMR (CDCI3): δ 9.39 (s, 1 H, ArH), 8.15 (m, 2 H, ArH), 7.90 (m, 2 H, ArH), 6.76 (s, 1 H, Br?CH-Ar).

Step 2) Preparation of 2-(Methylaminomethyl)quinoxaline AHP-9521/C1 -29The 2-(bromomethyl)quinoxaline (3.0 g, 13.4 mmol) was added portionwise to a stirring solution of methylamine (30%) in ethanol (100 mL) at 0°C. The reaction was stirred at 0°C for 2 hours, concentrated, and partitioned between 10% aqueous potassium carbonate/ethyl acetate. The organic phase was dried (MgSC>4), decolorized (charcoal) and concentrated. Purification was accomplished by eluting the sample through a short silica plug to yield 1.80 g (78%) of a brown oil. lH NMR (CDC13): δ 8.85 (s, 1 H, ArH), 8.10 (m, 2 H, ArH), 7.73 (m, 2 H, ArH), 4.15 10 (s, 2 H, NCH2Ar), 2.60 (s, 3 H, NCH3).

Step 3) Preparation of 3-Iodopropyl-4-nitrophenyl Ether To a stirring solution of 4-nitrophenol (10.0 g, 71.94 mmol) in tetrahydrofuran 15 (100 mL) at 0°C was added triphenylphosphine (22.6 g, 86.33 mmol), 3-iodopropanol (16.73 g, 89.93 mmol), and diethylazodicarboxylate (14.3 mL, 86.33 mmol). The resulting mixture was stirred at 25°C overnight. The mixture was partitioned between brine and ethyl acetate. The organic phase was dried and concentrated. The residue was triturated with 8:1 ether/ethyl acetate to induce the precipitation of 22 g of triphenylphosphine oxide which was separated by filtration. The filtrate was preabsorbed onto silica gel and flash-chromatographed (5:1 hexane/EtOAc) to afford 17.5 g (79%) of white solid product. lH NMR (CDCI3): δ 8.22 (d, J = 8.2 Hz, 2 H, ArH), 6.96 (d, J = 9.0 Hz, 2 H, ArH), 4.15 (t, J = 5.8 Hz, 2 H, OCH?). 3.37 (t, J = 7.0 Hz, 2 H, CH?I), 2.31 (m, 2 H, CH2CH2CH2I).

Step 4) Preparation of 2-[N-[3-(4-Nitrophenoxy)propyl]methylaminomethyl]quinoxaline To a stirred suspension of 2-(methylaminomethyl)quinoxaline (1.10 g, 6.35 mmol) and potassium carbonate (0.88 g, 6.35 mmol) in 2:1 acetonitrile/ethanol (40 mL) was added 3-iodopropyl-4-nitrophenyl ether (1.95 g, 6.35 mmol). The resulting mixture was heated at 85°C overnight, concentrated, and partitioned between ethyl acetate and AHP-9521/C1 -3010% aqueous potassium carbonate. The organic phase was dried (MgSCU), decolorized (charcoal), and concentrated to afford 1.86 g (83%) of product as a yellow semi-solid which was of sufficient purity to use in the next step. lH NMR (CDCI3): δ 8.95 (s, 1 H, ArH), 8.10 (d, J = 9.4 Hz, 2 H, ArH), 8.0 (m, 2 H, ArH), 7.72 (m, 2 H, ArH), 6.76 (d, J = 9.8 Hz, 2 H, ArH), 4.09 (t, J = 5.4 Hz, 2 H, OCH?). 2.67 (t, J = 5.2 Hz, 2 H, CH?N). 2.41 (s, 3 H, CH?N). 2.05 (m, 2 H, CH?CH?CH?).

Step 5) Preparation of 2-[N-[3-(4-Aminophenoxy)propyl]methylaminomethyl]quinoxaline A mixture of N-[(4-nitrophenoxy)propoxy[methyl]]aminomethylquinoxaline (1.75 g, 4.97 mmol) and PtO2 (0.14 g, 0.62 mmol) in ethanol (170 mL) was charged with 1 atmosphere H2(g). After 30 minutes, the mixture was filtered through solka floe and concentrated to afford crude product which was purified by HPLC to yield 1.18 g (74%) of a yellow oil. lH NMR (CDCI3): δ 9.00 (s, 1 H, ArH), 8.07 (m, 2 H, ArH), 7.73 (m, 2 H, ArH), 6.70 (d, J = 8.2 Hz, 2 H, ArH), 6.02 (d, J = 9.0 Hz, 2 H, ArH), 3.95 (t, J = 6 Hz, 2 H, OCH?). 3.89 (s, 2 H, NCH?Ar). 3.40 (brs, 2 H, NH?). 2.68 (t, J = 6.6 Hz, 2 H, CH?N). 2.33 (s, 3 H, NCH3), 1.99 (m, 2 H, CH?CH?CH?N).

Step 6) Preparation of N-[4-[3-[Methyl(2-quinoxalinylmethyl)amino]25 propoxy]phenyl]methanesulfonamide To a stirred solution of N-[(4-aminophenoxy)propoxy[methyl]]aminomethylquinoxaline (0.93 g, 2.89 mmol) and pyridine (0.47 mL, 5.78 mmol) in dichloromethane (20 mL) at 0°C under N2 was added dropwise methanesulfonyl chloride (0.25 mL, 3.21 mmol). The mixture was warmed to 25°C, stirred for 2.5 hours, and then partitioned between 10% aqueous NaHCC>3 and ethyl acetate. The organic phase was washed with brine, dried (MgSCty), decolorized (charcoal), and concentrated to afford 0.93 g (80%) of product as a yellow oil (one spot by TLC). The compound was treated with ethanolic HCl/ether to afford 0.75 g of the hydrochloride salt as a grey powder m.p. 165-170°C (dec.). -31 IE 904447 AHP-9521/C1 lH NMR (DMSO-D6): δ 9.42 (s, 1 H, NHSO2CH3), 9.20 (s, 1 H, ArH), 8.16 (m, 2 H, ArH), 7.95 (m, 2 H, ArH), 7.14 (d, J = 9.1 Hz, 2 H, ArH), 6.87 (d, J = 9.0 Hz, 2 H, ArH), 4.84 (m, 2 H, NCffc-Ar), 4.05 (t, J = 6 Hz, 2 H, OCH9-). 3.40 (m, 2 H, -CH9CH9CH9N). 2.93 (s, 3 H, NCH3). 2.87 (s, 3 H, NHSO2CH3), 2.26 (m, 2 H, CH9CH9CH9-N) IR (KBr): 2900 (NH) MS (m/e): 400 (M+, 5%), 257, 144 Anal (%) Calcd: C, 54.98; H, 5.77; N, 12.82. Found: C, 54.76, H, 5.87; N, 12.60.

AHP-9521/Cl

Claims (20)

1. A compound of formula (I): (I) 6 carbon atoms wherein R 1 is alkylsulfonamido of 1 to ary 1 sul fonami do of 6 to 10 carbon atoms, perf1uoroalkylsulfonamido of 1 to 6 carbon atoms, perf .1 uoroal kyl ami do of 1 to 6 carbon atoms, alkyl sulfone or alkylsulfoxide of 1 to 6 carbon atoms, 2 NC>2 , CN or 1 - ι mi dazoy 1 ; R is straight or branched alkyl chain of 1 to 6 carbon atoms; X is O, S, or 3 3 NR wherein R 5s H or a straight or branched alkyl chain of 1 to 6 carbon atoms; Y is Cl·^ or CHOH; Het is selected from wherein R 4 is H, -NHSO2 (C-^ to 0θ alkyl), -NHCOCC^ to Cg alkyl) or NO 2 ; and Z is 0, S, or NR 5 wherein R 5 is H, Cj to Cg alkyl or a 1 kyl su.l fonami do of 1 to 6 carbon atoms; or a pharmaceutical 1y acceptable salt thereof. AHP-9521/Ca

-332. A compound according to Claim 1 of formula (II) wherein R js H or methylsulfonamido or a pharmaceutically acceptable salt thereof.

3. N-[4-[2-Hydroxy-3-[methyl (2-quino1i nylmethy1 ) ami nolpropoxy ]phenyl Jmethanesu.1 fonami de or a pharmaceutically acceptable salt thereof.

4 . N-[4-[3-[Met.hyl(2-quinol inyl methyl )aminojpropoxyJpheny1]methanesulfonamide or a pharmaceutically acceptable salt thereof.

5. N-[4-[3-[Methyl(2-quinoxalinylmethyl/amino]propoxyjphenyljmethanesulfonamide or a pharmaceutically acceptable salt thereof.

AHP-9521ZC1 -346 · 1 -[ (Η-Benz imidazo.1 - 2-y 1 methy 1 Imethylaminoj3-(4-nitrophenoxy)-2-propanol or a pharmaceut! cal 1 y acceptable salt thereof.

7 . N- [ 4 - [ 3 - [ (1H-Benzimidazo.l - 2-yl methyl )met.hyl ami no ] -2-hydroxy prop oxy Ipheny 1 jmethanesul fonamide or a pharmaceutical 1y acceptable salt thereof.

8 . 1 - [ Me thy .1 ( 2 -qui no! inylmethyl ) ami no]- 3-(4nitrophenoxy)-2-propanol or a pharmaceutically acceptable salt thereof.

9. 1 — [C 2 — Benzofuranylmethyl Imethy1 amino] - 3 (4-nitrophenoxy ) -2-propanol or a pharmaceutical ly acceptable salt thereof.

10. N-[4 -[3-[(2-BenzofuranyImethy1lmethylami no]-2-hydroxypropoxyjphenyl Jmethanesulfonamide or a pharmaceutically acceptable salt thereof.

11. 1- [ ( 2-Benzoxazolylmethyl lmethylami no]-3-(4nitrophenoxy)-2-propanol or a pharmaceutica11y acceptable salt thereof.

12. A compound as claimed in any one of Claims 1 to 11 when in the form of a salt of an acid selected from hydrochloric, hydrobromic, phosphoric, sulfuric, sulfamic, nitric, methy1sulfonic, acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, lactic and naphthalenesulfonic.

13. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof which comprises one of the following AHP-9521/Cl -35a) reacting a compound of formula (II) wherein X and are as defined in Claim 1 with a compound of formula HN(R 2 )CH 2 Het 2. ... wherein R and Het are defined in Claim 1 to give compound of formula I wherein Y is CHOH; or b) reacting a compound of formula (III) a (IV) wherein R 1 and X are as defined in Claim 1 with a compound of formula (V) AHP-9521/Cl -362 wherein R and Het are as defined in Claim 1 to give a compound of formula I wherein Y is CHOH; or c) reacting a compound or formula (VI) where R 3 and X are as defined in Claim 1 and L is a leaving group, e.g an aryl- or alkyl-sulphonyloxy group such as p-tolyl- or methane -sulphony!oxy, with a compound of formula III as defined above, to give a compound of formula I wherein Y is CH 2 ; or d) reacting a compound of formula (IV) as defined above with a compound of formula (VII) whereing R , Het and L are as defined above to give a compound of formula I wherein Y is CH 2 ; or e) reacting a compound of formula (VIII) AHP-9521/Cl -371 2 wherein R , X and R are as defined in Claim 1 with A) a compound of formula L-CH 2 -Het ( IX ) or B) a compound of formula O=CH-Het (X) wherein L and Het are as defined above the reaction being carried out under reductive amination conditions when the compound of formula (X) is used, to give a compound of formula I; or f 1 reducing a compound of formula (XI) 12 . wherein X,Y, R , R and Het are as defined in Claim 1 to give a compound of formula I; or g) reductively aminating a compound of formula Het (XIII) AHP-9521/Cl -38wherein , X. Y and Het are as defined in Claim 1 with 3 3 an aldehyde of formula R CHO where R represents hydrogen or alkyl of 1 to 5 carbon atoms; or h) acylating a compound of formula I wherein is amino to give a corresponding compound of formula I wherein R^ .is an alkyl-, aryl- or perf 1 uoroalky.l-su 1 fonami do group or a perf .1 uoroalkyl ami do group; or i) acidifying a compound of formula to give an acid addition salt or neutral!zίng an acid addition salt of a compound of formula I to give the free base.

14. A process a) as claimed in Claim 13 when carried out in acetone or acetonitrile solvent.

15. A process c) as claimed in Claim 13 when carried out in the presence of a suitable base in acetone or acetonitrile.

16. A pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutical 1y acceptable salt thereof as claimed in any one of Claims 1 to 12 or a pharmaceutically acceptable salt., thereof or a pharmaceutically acceptable carrier and/or di 1uent.

17. A method of treating arrhythmia which comprises admiηistering an effective amount of a compound of the formula (I) as claimed in any one of Claims 1 to 12 or a pharmaceutically acceptable addition salt thereof.

AHP-9521/Cl -3918. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof substantially as hereinbefore described and illustrated in any one of Examples 1, step 4; 2, Step 4; 3, Step 2; 4; 5, Step 3; 6, Step 4; 7; 8 Step 3 and 9 Step 6.

19. A compound of formula I or a pharmaceutically acceptable salt thereof whenever prepared by a process as claimed in any one of Claims 13 to 15 and 18.

20. A compound of acceptable salt thereof arrhythmi a . formula I or a pharmaceutically for use as an agent to treat