WO1991009023A1 - N-heteroaralkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing class iii antiarrhythmic activity - 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-SUBSTTTUTED l-ARYT XY^-PROPANOLAMINE

AND PROPY AMTNE DERTVATTVES POSSESSING

C ASS m ANTTARRHYTHMTC ACTTVTTY

This is a continuation-in-part application of copending application U.S.S.N.

07/451,391, filed December 11, 1989.

BACKGROUND OF THE TNVENTTON

Class HI antiarrhythmic agents may be categorized as having the ability to markedly prolong dog Purkinje fiber action potential duration without producing signifi¬ cant 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 HI 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 con¬ duction velocity, generally without significant changes in the refractory period. Recent reviews of these agents are by: Bexton et al., Pharmac. Ther., 12, 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 HI antiarrhythmic activity of the dextro enantiomer of 4-(2-isopropylamino-l-hydroxyethyl)-methanesulfonamide (MJ-1999, Sotalol): Taggart et al., Clin. Sci., 62, 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]-ben- zamide 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 α- phenylethylamine 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. DESCRTPTTON OF THE TNVENTTON

In accordance with this invention, there is provided a group of antiarrhythmic agents classified by their pharmacological profile as Class m antiarrhythmic agents of the formula (I):

wherein R¹ is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 car¬ bon 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 1- imidazoyl; 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

wherein R⁴ is H, -NHSO2 (Ci to alkyl), -NHCO(Cι to CO alkyl) or NO2- and Z is O,

S, or NR⁵ wherein R⁵ is H, Ci to C(^~ 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 and C3F7. Examples of aryl are phenyl, naphth-1-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)

CH₃

/

wherein R¹ is NO₂ or methylsulfonamido; Y is CH₂ or CHOH; and Het is selected from 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 N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino]propoxy]phenyl]methane- sulfonamide;

N-[4-[3-[methyl(2-qumolinylmethyl)aπώιo]propoxy]phenyl]methanesulfonamide;

N-[4-[3-[methyl(2-quinox_dmyl-methyl)an__ino]propoxy]phenyl]methanesulfonamide;

l-[(lH-benz_midazol-2-y]_methyl)methylamino]-3-(4-nitrophenoxy)-2-propanol;

N-[4-[3-[(lH-benzimidazol-2-ylmethyl)methy]__umno]-2-hydroxypropoxy]phenyl]- methanesulfonamide;

l-[methyl(2-quiBo_inyl-memyl)amino]-3-(4-nitrophenoxy)-2-propanol;

l-[(2-benzofu-ranylmethyl)methylamino]-3-(4-nitrophenoxy)-2-propanol;

N-[4-[3-[(2-benzofuranyl_methyl)memylamino]-2-hydroxypropoxy]phenyl]methane- sulfonamide;

l-[(2-benzox.izolylmethyl)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 theηgjjf which possess the activity dis- cussed below. In particular, it encompasses racemic modifications and any optical iso- mers 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 invention. 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 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 inven¬ tion are prepared directly by neutralization of the free base. These physiologically ac¬ ceptable salts may be formed with organic or inorganic acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, sulfamic, nitric, methylsulfonic, acetic, maleic, suc- 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)CH Het (_H)

wherein R² and Het are as defined above to give a compound of formula (I) wherein Y is CHOH; or b) reacting a compound of formula

wherein R¹ and X are as defined above, with a compound of formula

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

wherein R¹ and X are as defined above and L is a leaving group, e.g. an aryl- or alkyl- sulphonyloxy 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 reacting a compound of formula (IV) as defined above with a compound of formula

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

wherein R¹, X and R² are as defined above with A) a compound of formula

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

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

wherein 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 perfluoroalkyl-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 reac¬ tion of an appropriately substituted aryl epoxide with the required secondary amine in solvents such as acetone or acetonitrile:

wherein R¹, R², Het and X are as defined above.

When Y is CH2, the compounds can be prepared by the reaction of an appropri¬ ately substituted alkyl halide with the required secondary amine in the presence of a suit¬ able 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 pre¬ pared 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. Arterial 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)

8 + 2* 25 + 7 *

* Current threshold in mA necessary to induce fibrillation. • 2 to the 6 animals defibrillated spontaneously Cardiac Electrophysiology

The compounds of this invention display a Class Dl antiarrhythmic profile. The Class HI 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; KC14; CaCh, 2; MgCh, 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 KC1 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 (V_max) was obtained using an analog differentiator circuit, coupled to a peak-hold circuit that retained the recorded value of Vmax f°^r 30 to 70-msec. Action potential and V_max tracings were displayed on a storage oscilloscope, and photographed for later analysis. In addition, chart paper recordings of V_max were obtained using the peak-hold device output. Fresh 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 μM in appropriate volumes of normal Tyrode's solution for evaluation.

Action potential (AP) parameters measured included: diastolic take-off potential (or activation voltage, V(_ac_t)ϊ AP overshoot (V₀s). AP duration measured as the time taken to repolarize to -20 mV (APD-20 -60 mV (APD-60), and -80 mV (APD.so); and maximal upstroke velocity (V_max). An increase in APD-₆0 that occurred without a significant change in V_maχ 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. Refractory periods of the right atrium and right ventricle (AERP and VERP) were 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 electrophysiologic parameters. An increase in ERP that occurred without a significant decrease of CT was taken, by definition to indicate "in vivo" Class HI antiarrhythmic activity.

The results of the assays are set forth in the table below:

* Paced at 500 msec

Ψ Dosed at 10 mg kg in anesthetized dog and at 10 μM 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 estab¬ lished as antiarrhythmic agents useful in the treatment of cardiac arrhythmia and condi¬ tions 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, inter- nasal, 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

SUBSTITUTE SHEET arrhythmatic dysfunction. The specific dosage regimen for a given patient will depend upon age, pathological state, severity of dysfunction, size of the patient, etc. Oral admin¬ istration 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 col¬ oring. 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.

EXAMPLE 1

l-r H-Benzimidazol-2-vlmethvl)methvlamino1-3-f4-nitroDhenoxvV 2-nronanol Dihvdrochloride

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 (MgSO₄), and concentrated to afford 27.5 g of product (83%) as a red oil of sufficient purity to use in the next step.

1H NMR (CDCI3): 5 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-). Step 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 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, -OCH2-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 (MgSO_ 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.

1H NMR (CDCI3): δ 7.56 (m, 2H, Ar_H), 7.22 (m, 2H, ArH), 4.07 (s, 3H, CH2NHCH3), 2.51 (s, 3H, NHCH3).

Step 4) Preparation of l-[(lH-Ben_rimidazol-2-ylmethyl)methylamino]-3-(4-nitro- phenoxy)-2-propanol Dihydrochloride 2-(Met-hyla_a_ nomethyl)ben._imidazole (0.459 g, 3.07 mmol) was added to a solu¬ tion 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 product as a pale yellow solid dihydrochloride salt m.p. 207-209°C.

-H 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-r4-r3-rπH-Benzimidazol-2-vlmethvnmethvlaminol-2-hvdroxv- 'propoxvlphenvlmethanesulfonainide

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^βC, was slowly added stannous chloride (48 g, 212 mmol). After stirring for 20 minutes at 55°C, the mixture was cooled to 0°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. ^!H NMR (CDCI3): δ 7.05 (m, 4H, ArH), 6.4 (m, 1H, OCH₂-CH=CH₂), 5.70 (m, 2H, CH CH=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.

~π 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 chlo- 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, Jι=5.54 Hz, J₂=2.98 Hz, 1H, epoxide CH2), 3.90 (dd,

H ι=5.54, J₂=5.78 Hz, 1H, epoxide CH₂), 3.35 (m, 1H, epoxide CH), 2.94 (s, 3H, NHSO2CH3), 2.90 and 2.76 (2m, OCH2) IR (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-hydroxy- propoxy]phenyl]methanesulfonamide

2-(Methylaιτ_inomethyl)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-methanesulfon- 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 analyti¬ cally pure product m.p. 163-165^βC.

-Η. 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-rMethvK2-quinolinvlmethvnamino1.3-f4-nitrophenoxv^ 2-propanol Dihvdrochloride Step 1) Preparation of 2-(Methylaminomethyl)quinoline

2-Chloromethylquinoline hydrochloride (3.00 g, 14.01 mmol) was suspended in 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 (MgSO_ and concentrated to afford 2.22 g (92%) of pure product as a brown oil.

¹H NMR (CDCI3): 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-[Melhyl(2-quinoliny_-memyl)armno]-3-(4-nitrophenoxy)-

2-propanol Dihydrochloride

2-(Methylaminomethyl)quinoline (1.76 g, 10.22 mmol) was added to a solution of 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 col¬ umn chromatography (3% MeOH - CH2CI2) and then treated with ethanolic HCl and ether to afford 0.510 g (13%) of product as the white solid dihydrochloride salt m.p. 154-157°C.

-R 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-CH2-N), 3.01 (s, 3H, NCH3)

IR (KBr, cm-¹): 3260 (NH+) 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.

EXAMPLE 4

N-r4-r3-rr2-Ouinolinvlmethvl methvlamino1-2-hvdroxvpropoxv1- phgnγπmethanesu.fpnamide

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 1,2- epoxy-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 analyti¬ cally pure product m.p. 118-120^βC 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, lH, 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. EXAMPLE 5

l-rf2-Benzoxazolvlmethvnmethvlam.no1-3-f4-nitronhenoxv,- 2.nropanol Hvdrochloride

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 (MgSQφ) and concentrated to afford 3.99 g (65%) of product as a brown oil which was used directly in the next step.

^!H 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.

-E. NMR (CDCI3): δ 7.72 (m, 1H, ATH), 7.54 (m, 1H, ArH), 7.33 (m, 2H, ArH), 4.08

(s, 2H, CH2NHCH3), 2.56 (CH2NHCH3). Step 3) Preparation of l-[(2-Benzoxazolylmethyl)methylamino]-3-(4-nitrophen- oxy)-2-propanol Hydrochloride

2-(Methylaminomethyl)benzoxazole (1.86 g, 11.53 mmol) was added to a solu- tion of 1 ,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% MeOH- CH2CI2) then treated with ethanolic HCl and ether to afford 2.12 g (70%) of pure product as the off-white solid hydrochloride salt m.p. 214-216^*C.

-H NMR (DMSO-d6): δ 8.20 (d, J=9.13 Hz, 2H ArH), 7.84 (dd, Jι=7.67 Hz,

J₂=.415 Hz, 1H, ArH), 7.80 (dd, Jι=8.50 Hz, J₂=1.25 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.

EXAMPT.E fi

N-r4-r3-rf2-Benzofuranvlmethvnmethvlamino1-2-hvdroxvpropoxv1- phenvnmethapesnIfonam.de

Step 1) Preparation of Benzofuran-2-methanol

1 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.

-B. 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 chlo¬ ride (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 (MgSO₄) and concentrated to af¬ ford 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.

*H NMR (CDCI3): δ 7.52 (m, 2H, ArH), 7.27 (m, 2H, ArH), 6.73 (s, 1H, CH=C-), 4.69 (s, 2H, CH2CI).

Step 3) Preparation of 2-(Methylaminomethyl)benzofuran 2-(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 warmed to room temperature and stirring was contin¬ ued for 72 hours. The mixture was diluted with water and extracted with methylene chlo- ride. The organic phase was dried (MgS04) and concentrated to afford crude product which was purified by flash column chromatography (10% MeOH/CH2θ2) to afford 1.00 g (37%) of pure product as a pale yellow oil.

1H 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-hydroxy- propoxy]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 acetoni¬ trile (12 mL). The reaction mixture was heated at reflux for 48 hours, cooled and concen¬ trated in vacuo. The residue was purified by chromatotron (10% MeOH/CH2θ2) 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.

-K 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. EXAMPI E 7

1-rr2-Benzofιιranvlmethvnmethvlamino1-3-r4-nitronhennxv

2-propatwl flγdrøcMpr?dg

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 pure hydrochloride salt as a pale yellow solid m.p. 208-209^βC.

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=3.86Hz, 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 fi N-r4-r3-rMethvir2-quinolinylmethyl)amino1propoxy1phenvnmethanesulfonamide

Step 1) Preparation of 2-j^-[3-(4-Nitrophenoxy)propyl]memylaminomethyl]- quinoline To a stirred suspension of 2-(methylaminomethyl)quinoline, prepared by the pro¬ cedure 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 3- chloropropyl-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 (MgSO4), and concentrated to afford an oil. The product was purified by HPLC (10% MeOH/OfeCh) 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, -NΗ2),

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]- phenyljmethanesulfonamide

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 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with ice chips and extracted with ethyl acetate. The organic phase was dried (MgSQ-j), 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.

^lR 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-πVIethv 2-αuinoxalinylmethvI)amino1propoxy1phenvnmethanesulfonamide

Step 1) Preparation of 2-(Bromomethyl)quinoxaline

To a stirring solution of 2-methylquinoxaline (20.0 g, 155 mmol) and benzoyl peroxide (3 g, 12 mmol) in carbon tetrachloride (800 mL) was added -l,3-dibromo-5,5- dimethyl 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, BrCIfe-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 The 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 (MgSθ4), 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 (s.2 H. NOfrAr).2.60 (s.3 H. NCH .

Step 3) Preparation of 3-Iodopropyl-4-nitrophenyl Ether

To a stirring solution of 4-nitrophenol (10.0 g, 71.94 mmol) in tetrahydrofuran (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 pre- absorbed 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, OCH2), 3.37 (t, J = 7.0 Hz, 2 H, CH2D, 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 10% aqueous potassium carbonate. The organic phase was dried (MgSO4), 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 (CDC1₃): 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, OCΗ2), 2.67 (t, J = 5.2 Hz, 2 H, CH2N), 2.41 (s, 3 H, CH3N), 2.05 (m, 2 H, CH2CH2CH2).

Step 5)

of2-[ -[3-(4-Aminophenoxy)propyl]methylaminomethyl]- quinoxaline

A mixture of N-[(4-nitrophenoxy)propoxy[methyl]]aminomethylquinoxaline

(1.75 g, 4.97 mmol) and Ptθ2 (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, NCHsAr), 3.40 (brs, 2 H, NH2), 2.68 (t, J = 6.6 Hz, 2 H, CH2N). 2.33 (s, 3 H, NCH3), 1.99 (m, 2 H, CH2θl2CH2N).

Step 6) Preparation of N-[4-[3-[Methyl(2-quinoxalinylmethyl)amino]- 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 NaHCO3 and ethyl acetate. The organic phase was washed with brine, dried (MgSO4), 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). 1H 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, NCH?-Ar 4.05 (t, J = 6 Hz, 2 H, OCR--). 3.40 (m, 2 H, -CH₂CH₂CH₂N), 2.93 (s, 3 H, NCH3), 2.87 (s, 3 H, NHSO2CH3), 2.26 (m, 2 H, CH7CH9CH9-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.

Claims

We claim:

1. The compounds of formula (I):

wherein R¹ is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 car¬ bon 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 1- imidazoyl; 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

wherein R⁴ is H, -NHSO2 (Ci to C6 alkyl), -NHCO(Cι to C alkyl) or NO_2; and Z is O, S, or NR⁵ wherein R⁵ is H, Ci to Cβ alkyl or the alkylsulfonamido of 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1 of formula (H)

(π) wherein R¹ is NO2 or methylsulfonamido; Y is CH2 or CHOH; and Het is selected from the group consisting of

wherein R⁴ is H or methylsulfonamido and the pharmaceutically acceptable salts thereof.

3. The compound according to claim 2 N-[4-[2-hydroxy-3-[methyl(2-quino- linylmethyl)amino]propoxy]phenyl]methanesulfonamide and the pharmaceutically acceptable salts thereof.

4. The compound according to claim 2 N-[4-[3-[methyl(2-quinolinyl- memyl)amino]propoxy]phenyl]methanesulfonamide and the pharmaceutically acceptable salts thereof.

5. The compound according to claim 2 N-[4-[3-[methyl(2-quinoxalinyl- methyl)amino]propoxy]phenyl]methanesulfonamide and the pharmaceutically acceptable salts thereof.

6. The compound according to claim 2 l-[(lH-benzimidazol-2-yl- methyl)methylamino]-3-(4-nitrophenoxy)-2-propanol and the pharmaceutically acceptable salts thereof.

7. The compound according to claim 2 N-[4-[3-[(lH-benzimidazol-2-yl- methyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide and the pharma¬ ceutically acceptable salts thereof.

8. The compound according to claim 2 l-[methyl(2-quinolinyl- methyl)amino]-3-(4-nitrophenoxy)-2-propanol and the pharmaceutically acceptable salts thereof.

9. The compound according to claim 2 l-[(2-benzofuranyl- methyl)methylamino]-3-(4-nitrophenoxy)-2-propanol and the pharmaceutically acceptable salts thereof.

10. The compound according to claim 2 N-[4-[3-[(2-benzofuranyl- methyl)methylamino]-2-hydroxypropoxy]phenyl]methanesulfonamide and the pharma¬ ceutically acceptable salts thereof.

11. The compound according to claim 2 l-[(2-benzoxazolyl- methyl)methylamino]-3-(4-nitrophenoxy)-2-propanol and the pharmaceutically acceptable salts thereof.

12. The process for producing the compounds of formula (I)

wherein R¹ is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 car¬ bon 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 1- imidazoyl; 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

wherein R⁴ is H, -NHSO2 (Ci to Cβ alkyl), -NHCO(Cι to Cβ alkyl) or NO_2; and Z is O, S, or NR⁵ wherein R⁵ is H, Ci to Cβ alkyl or the alkylsulfonamido of 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof which comprises reaction of an appropriately substituted aryl epoxide of formula

wherein R¹ and X are as defined above with the appropriately substituted secondary amine

R² /

HN Het

wherein R² and Het are as defined above in acetone or acetonitrile.

13. The process for producing the compounds of formula (I)

wherein R¹ is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 car¬ bon 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 1- imidazoyl; 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

wherein R⁴ is H, -NHSO2 (Ci to Cβ alkyl), -NHCO(Cι to Cβ alkyl) or NO2; and Z is O, S, or NR⁵ wherein R⁵ is H, Ci to C alkyl or the alkylsulfonamido of 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof which comprises reacting the appropriately substituted alkyl halide of structure

wherein R¹ and X are as defined above and W is chlorine or bromine with the appropri¬ ately substituted secondary amine of structure

in the presence of a suitable base in acetone or acetonitrile.

14. A pharmaceutical composition having antiarrhythmic properties which comprises and effective amount of a compound of the formula (I) of claim 1 or its physio- logically tolerated acid addition salt and a pharmaceutically acceptable carrier and/or diluent.

15. A method of treating arrhythmia which comprises administering an effec¬ tive amount of a compound of the formula (I) of claim 1 or its pharmaceutically acceptable acid addition salt.