KR900006902B1 - Antiarrhythmics - Google Patents

Abstract

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Description

Antiarrhythmics

The present invention relates to a characteristic sulfonamide, which is an antiarrhythmic agent, and an intermediate thereof.

The compounds of the present invention increase the nonresponsiveness to premature stimulation by prolonging the action potential period of myocardium and conductive tissue. Thus, they are Class III antiarrhythmic agents according to Vaughan William's classification (Anti-Arrhythmic Action, E. M. Vaughan Vlliams, Academic Pres, 1980). They are effective for atrial, ventricular and conductive tissues both in vitro and in vivo and are useful for the prevention and treatment of various ventricular and ventricular arrhythmias including atrial and ventricular fibrillation. They do not change the rate at which they stimulate stimulation, resulting in lower arrhythmia or worsening of arrhythmia than current medications (usually class I), and much less neurological side effects. In addition, some of the compounds have positive metabolic activity, which is particularly beneficial for patients with impaired cardiac pumping.

The present invention provides compounds of the following general formula and salts thereof.

Wherein R is —NO ₂ , —NH ₂ or —NHSO ₂ (C ₁ to C ₄ alkyl): R ¹ is C ₁ to C ₄ alkyl and “Het” is a group of the general formula

[Where R ² is H, CH ₃ or C ₂ H ₅ ; R ³ is —NO ₂ , —NH ₂ or —NHSO ₂ (C ₁ to C ₄ alkyl): X is O, S or NR _4, wherein R ⁴ is H or CH ₃ ; When one of R, R and R ³ is -NO ₂ , the other is not -NH ₂ .

Compounds of formula (A) wherein R and R ³ are -NHSO ₂ (C ₁ to C ₄ alkyl) have activity as antiarrhythmic agents. The remaining compounds are synthetic intermediates.

The present invention also provides an antiarrhythmic agent of the general formula and pharmaceutically acceptable salts thereof.

Wherein R is —NHSO ₂ (C ₁ to C ₄ alkyl): R ¹ is C ₁ to C ₄ alkyl, and Het is a group of the general formula

[Where R ² is H, CH ₃ or C ₃ H ₅ ; R ³ is —NHSO ₂ (C ₁ to C ₄ alkyl) and X is O, S or NR ₄ , where R ⁴ is H or CH ₃ .

In compound (I), R is preferably -NHSO ₂ CH ₃ , R ¹ is preferably CH ₃ or C ₂ H ₅ , R ² is preferably H or CH ₃ , and R ³ is preferably Is -NHSO ₂ CH ₃ , and X is preferably 0 or S.

Substituent R ³ is preferably present at position 6 or 7 when "Het" contains a quinolyl group, and in other cases (i.e., when the benzene ring is bonded to a heterocyclic ring of 5 atoms), 5 or 6 It is preferable to exist at position 1.

Each preferred compound has the structure

Salts of pharmaceutically acceptable compounds of formula (I) are hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, malate, fumarate, lactate, tarta Acid addition salts formed from acids forming non-toxic acid addition salts containing pharmaceutically acceptable anions such as late, citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate salts Include. Salts can be prepared by conventional techniques.

To assess the atrial nonreactive effect of the compound, the right atrium of the guinea pig is placed in a bath containing physiological saline and one end is connected to a force transducer. Stimulate the tissue at 1 Hz using field electrodes. An effective no-reactor (ERP) is measured by inducing premature stimulation (S ₂ ) after every eight basic stimuli (S ₁ ). Lead S ₂ so that the reproducibility of the delivered reaction thereby increasing the S ₁ S ₂ coupling interval to naelttae gradually. This is defined as ERP. The concentration of compound needed to increase ERP at 25% ED ₂₅ is then measured. ERP of the right papillary muscle of guinea pigs cultured in physiological saline is also measured. The bipolar electrode plate is used to stimulate the muscle at one end and record the radiation transmitted from the opposite end to the monopolar surface electrode plate. ERP is measured using external stimulation techniques as described above. The conduction time (ie the time required for the shock to propagate along the muscle) is obtained from the digital storage oscilloscope by measuring the distance between the artificial stimulus and the peak of the radiation.

Atrial and ventricular ERP are also measured in dogs anesthetized or conscious by external stimulation techniques at a constant rate.

The compound of formula (I) may be administered by itself but is generally administered in combination with a pharmaceutical carrier selected by the planned route of administration and standard pharmaceutical practice. They can be administered prophylactically to patients suffering from arrhythmias and also to patients who may have arrhythmias. For example, they may be administered orally in tablet form containing excipients such as lactose starch, or capsules containing themselves or mixtures with excipients, or elixirs or suspensions containing flavoring or coloring agents. . They can be injected intravenously, intramuscularly or subcutaneously. For intradermal administration, sterile aqueous solutions containing sufficient salt or other solutes, such as glugoose, are most often used to make isotonic solutions.

Involving atrial and ventricular fibrillation. For administration to patients in need of curative or prophylactic treatment of cardiac lesions such as ventricular and gastric ventricular arrhythmias, oral dosages of Formula (I) compounds range from 2 to 150 mg per day for adults weighing 70 kg and a daily dose of 4 Administration is divided into circuits. Dosages for intravenous administration may optionally range from 1.0 to 20 mg per dose. Severe deep veins can be cured, preferably by the intravenous route, to achieve the effect of rapidly converting to normal rhythm. Thus, for a typical adult patient, 2 to 50 mg of active substance in a pharmaceutically acceptable suitable excipient or carrier per tablet or capsule will be included. Depending on the weight and condition of the patient to be treated, the attending physician may vary.

Accordingly, the present invention provides a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above together with a pharmaceutically acceptable diluent or carrier.

The present invention also provides a method of preventing or alleviating a deep vein in a human by administering to a human an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above.

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, used as a medicament, in particular as an antiarrhythmic agent.

The present invention provides a method of using a compound of formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for preventing or alleviating deep vein.

A compound represented by the general formula (I) can be prepared by general route of the following (1) The first route is C ₁ to C ₄ alkane sulfonyl chloride or bromide or a C ₁ to C ₄ alkane formula by using the acid anhydride (A Acylation of compounds wherein R and / or R ³ is NH ₂ . If both R and R ³ are -NH ₂ , at least 2 equivalents of acylating agent is required and, of course, R and R ³ of the final product will be the same.

The reaction is typically carried out at room temperature and optionally in the presence of an acid acceptor such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of acid acceptors is particularly useful when using alkanesulfonyl chloride or bromide. In fact it is especially common to carry out the reaction with alkanesulfonylchloride in pyridine. The product of formula (I) can then be separated and purified by conventional methods.

Starting materials for such acylation reactions are usually useful as follows.

Wherein R and “Het” are as defined in formula (I) and Q is a leaving group such as chloro, bromo, iodo or methanesulfonyloxy.

R, Het and Q are as defined in (a) above. (C) Routes (a) and (b) also indicate that substituent R ³ on “Het” is nitro instead of C ₁ to C ₄ alkanesulfonamido. It can be carried out using a starting material, thus producing a di-nitro intermediate which can be reduced to a diamino starting material such as starting material of general formula (A) wherein R and R ³ are amino by catalytic hydrogenation.

Wherein R is C ₁ to C ₄ alkyl, "Het" of the first stage is a nitro-substituted heterocycle as defined in formula (A), and Q is a departure as defined in (a) above Group.

The starting materials used in the methods (a) to (d) can be known compounds or compounds which can be prepared by conventional techniques by the manner described in the following preparations.

(2) The two-time route of compound (I) is described as follows.

Wherein R ¹ is C ₁ to C ₄ alkyl and “Het” is as defined in formula (I), Q is chloro, bromo, iodine, C ₁ to C ₄ acansulfonyl oxy (preferably Methanesulfonyloxy), benzenesulfonyl oxy or toluenesulfonyloxy.

The reaction is typically carried out at or below the refueling temperature in the organic solvent. The presence of an acid acceptor is optional but is most useful when Q is Cl, Br or I. Typical acid acceptors are pyridine, triethylamine, potassium carbonate, and sodium bicarbonate. Starting materials are known compounds or can be obtained conventionally.

The following examples describe the preparation of compounds of formula (I). All temperatures are in degrees Celsius.

Example 1

N-methyl-N- (3-methyl-5-methanesulfonamidobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

Methanesulfonyl chloride (0.21 g, 1.85 mmol) is added in pyridine (7 ml) and the solution is stirred at room temperature for 60 hours. The solvent is evaporated and the residue is triturated with toluene. Toluene was decanted and the residue was stirred with aqueous sodium bicarbonate solution, the precipitate was collected by filtration and recrystallized from methanol to give the title compound (yield 0.38 g, melting point 142 to 143 5 ° C.).

Elemental Analysis for C ₂₁ H ₂₇ N ₃ O ₅ S ₂

Found (%): C: 54.4, H: 5.8, N: 9.1

Calculated Value (%): C: 54.2, H: 5.85, N: 9.0

Example 2

N-methyl-N- (5-methanesulfonamidobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

Methanesulfonyl chloride (0.76 g, 6.6 mmol) was added N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-amino phenethylamine in pyridine (25 ml) (see Preparation Example 3-0.9 g, 3.0 mmol) is added to the solution and the mixture is stirred at room temperature for 18 hours. The solvent is then evaporated and the residue is distilled off with an aqueous sodium bicarbonate solution and extracted three times with methylene clover. The combined organic extraction rates are dried (MgSO ₄ ) and evaporated, and the residue is purified by chromatography on silica eluting with ethyl acetate. Fractions containing product were combined and evaporated and the resulting solid was recrystallized from ethyl acetate / methanol to give the title compound (yield 0.35 g, melting point 177 to 179 ° C.).

Elemental Analysis for C ₂₀ H ₂₅ N ₃ O ₅ S ₂

Found (%): C: 53.2, H: 5.7, N: 9.0

Calculated Value (%): C: 53.2, H: 5.6, N: 9.3

Example 3

N-methyl-N- (5-methanesulfonamidebenzoxazin-2-ylmethyl) -4-methanesulfonamidophenethylamine

N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (see Preparation Example 1C-0.5) in methanesulfonyl chloride (0.38 g, 3.3 mmol) and pyridine (20 ml) g, 1.5 mmol) ol Reaction together under conditions similar to those of Example 2 to give the title compound (yield 0.25 g from ethanol, melting point 174-176 ° C.).

Elemental Analysis for C ₁₉ H ₂₄ N ₄ O ₅ S ₂

Found (%): C: 50.4, H: 5.1, N: 12.4

Calculated Value (%): C: 50.4, H: 5.35, N: 12.4

Example 4

N-methyl-N- (6-betansulfonamidobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

N-methyl-N- (6-aminobenzofur-2-ylmethyl) -4-aminophenethylamine in methanesulfonyl chloride (0.21 g, 1.8 mmol) and pyridine (3 ml) (see Preparation Example 2-0.24 g , 0.82 mmol) were reacted together under similar conditions as in Example 2 to give the title compound as an oil. (Yield 0.18 g)

Elemental Analysis for C ₂₀ H ₂₅ N ₃ O ₅ S ₂

Found (%): C: 53.0, H: 5.7, N: 9.1

Calculated Value (%): C: 53.2, H: 5.6, N: 9.3

Example 5

N-methyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4-methanesulfamidophenethylamine

N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethylamine in methanesulfonyl chloride (0.15 g, 1.3 mmol) and pyridine (20 ml) (see Preparation Example 4-0.17 g, 0.37 mmol) were reacted together under conditions similar to those of Example 2 to give the title compound (yield 0.70 g from ethyl acetate, melting point 163 to 165 ° C.).

Elemental Analysis for C ₂₁ H ₂₆ N ₄ O ₄ S (%):

Found: C: 54.3, H: 5.45, N: 12.1.

Calculated Value: C: 54.5, H: 5.7, N: 12.1.

Example 6

N-methyl-N- [5-methanesulfonamido-2-benzo [b] thienylmethene-4-methanesulfonaidophenethylamine

N-ethyl-N- (5-amino-2-benzo [b] thienylmethyl) -4-aminophenethylzinc (0.26 g, see Example 13) according to the method of example 2 to methanesulfonyl in pyridine Treatment with chloride (0.23 g) affords the title compound. (Yield 0.167 g, Melting point 175-177 ° C.)

Elemental Analysis for C ₂₀ H ₂₅ N ₃ O ₄ S ₃ (%):

Found: C: 50.99, H: 5.39, N: 8.93.

Calculated Value: C: 51.37, H: 5.39, N: 8.99.

Example 7

N-ethyl-N- (6-detansulfonamidoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine hydrochloride

Similar to the method of Example 2, methanesulfonylchloride (0.1 g, 1.29 mmol) was added N-ethyl-N- (6-aminoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine in pyridine. (See Preparation Example 11 (B) -0.51 g, 1.23 mmol) to give the free base of the title compound as a rubber. The rubber is dissolved in ethyl acetate and the solution is distilled off with ethereal hydrogen chloride and evaporated to dryness. The residue was triturated with ether to give the title compound as a bubble (yield 0.06 g, melting point 96 ° C.).

Elemental Analysis for _{C 22 H 28 N 4 O 4} S 2 · HCl · H 2 O (%)

Found: C: 50.2, H: 55, N: 10.0

Calculated Value: C: 49.75, H: 5.9, N: 10.5.

Example 8

N- (6-methanesulfonamido-2-quinolylmethyl) -N-methyl-4-methane-sulfonamidophenethylamine

4- [2- (methylamino) ethyl] methanesulfonanilide (0.228 g, 1 mmol-see Preparation Example 14 (B)) and 2-chloromedin-6-methane-sulfonamidoquinoline (0 135 g, 0.5 mmol) (See Preparation Example 12 (D)) is heated for 4 hours at reflux in ethanol solution (5 ml). The solvent is then evaporated in vacuo and the residue is dissolved in methylene chloride, washed with water and dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting rubber is purified by column chromatography on silica eluting with methylene chloride containing methanol (0% to 1%). The product-containing fractions were combined and evaporated in vacuo to give a bubble which was recrystallized from ethanol to give the title compound which was spectroscopically identified as the product of Example 5 (yield 0.45 g, melting points 165 to 166).

The following preparation examples describe preparation examples of the novel starting materials. All temperatures are in degrees Celsius.

Preparation Example 1

(A) 2-chloromethyl-5-nitrobenzoxazole

2-amino44-nitrophenol (10 g, 65 mmol) and ethyl chloroacetimidae hydrochloride (15.4 g, 97.5 mmol) are heated in reflux at ethanol (100 ml) for 18 hours and then the solvent is evaporated off in vacuo. The residue is recrystallized from ethanol to give the title compound (yield 9.0 g, melting point 216-217 ° C.).

Elemental Analysis for C ₈ H ₅ ClN ₂ O ₃ (%)

Found: C: 45.15, H: 2.3, N: 13.25

Calculated Values: C: 452, H: 2.4, N: 13.2.

(B) N-methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethyl-amine

2-chloromethyl-5-nitrobenzoxazole (285 g, 134 mmol), N-methyl-4-nitrophenethylamine (J OC, [1956], 45) (2.2 g, 12.2 mmol) potassium carbonate (1.85 g, 13.4 mmol) and sodium iodide (2.0 g, 13.4 mmol) are heated under reflux in acetonitrile (50 ml) for 3 days. The solvent is then evaporated, the residue is diluted with water and extracted three times with methylene chloride. The combined organic extracts are washed with water, dried (MgSO ₄ ), filtered and evaporated to dryness. The resulting oil is diluted with ether and the supernatant is decanted and evaporated to dryness to give an orange solid which is recrystallized from isopropanol to give the title compound (yield 0.80 g).

¹ HN.mr (CDCl ₃ ): delta = 8.6 (d, 1H); 8.3 (dd, 1H); 8.1 (d, 2H); 7.6 (d, 1 H); 7.35 (d, 2H); 3.95 (s, 2 H); 2.95 (q, 2 H); 2.85 (q, 2 H); 2.5 (s, 3H) ppm

(C) N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine

N-methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethyl-amine (0.78 g, 2.2 illi) in ethanol (50 ml) containing Raney nickel (0.1 g) Mole) was stirred for 18 hours under hydrogen atmosphere (50 psi = 344.7 kPa), all starting materials were consumed as thin layer chromatography [silica chromatography plate using methylene chloride / methanol (19: 1) as solvent]. Appeared in the analysis. The reaction mixture is then filtered and evaporated to afford an oil, azeotropic with toluene and triturated with ether. The decanted ether is evaporated to give the title compound as an oil which is used directly without further purification (yield 0.45 g).

¹H-Nmr (CDCl₃; δ = 7.25 (d, 1H); 6.95 (dd, 3H); 6.65 (dd, 1H); 6.6 (d, 2H); 3.85 (s, 2H); 2.7 (s, 4H); 2.4 (s, 3H)

[Production Examples 2 to 4]

Compounds of Preparation Examples 2 and 3 had corresponding di-nitro compounds (see Preparation Examples 6 and 5) using reaction times of 4 and 17 hours, respectively, and H ₂ / Raney Ni / ethanol / 50p.si / room temperature. ) Is prepared similarly to Preparation Example 1 (c). The compound of Preparation Example 4 was prepared similarly to Preparation Example 1 (c), but was reacted for 3 hours using H ₂ / Pd / C in ethanol at 30 p.si and the related di-nitro starting material was prepared. This is the target of Example 8.

30p.s.i. corresponds to 206.8 Kpa, and 50p.s.i. corresponds to 344.7 KPa.

Production Example 5

(A) 4- (isopropylideneamineoxy) nitrobenzene

A solution of propanone oxime (30 g, 0.4 mol) in anhydrous tatrahydrofuran (300 ml) is slowly added to a suspension of hydrogenated sodium hydride (10.8 g, 0.45 ol) in anhydrous tetrahydrofuran (50 ml). After gas evolution is complete, dimethyl sulfoxide (100 ml) and 4-fluoronitrobenzene (57.85 g, 0.41 mol) are added and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is then poured into water and extracted three times with ether. The combined ether extractions are washed with water, dried (MgSO ₄ ) and evaporated to afford the title compound which is granulated in hexanes and filtered (yield 67 g). Sample 7g is recrystallized from ethanol (yield 5g, melting point 104-106 ° C).

Elemental Analysis for C ₉ H ₁₀ N ₂ O ₃ (%):

Found: C: 55.6, H: 5.05, N: 14.35

Calculated Value: C: 55.7, H: 5.2, N: 14.4.

(B) 2-ethyl-5-nitrobenzofuran

4- (isopropylideneamineoxy) nitrobenzene (60 g, 0.309 mol) is added to glacial acetic acid (530 ml) containing gaseous hydrogen chloride (25 g) and the mixture is heated at 100 ° C. for 18 hours. The solvent is removed and the residue is azeotropic with cyclohexane to give an oil which is diluted with water and extracted three times with methylene chloride. The combined organic extracts are washed with 10% aqueous sodium hydroxide solution and water, dried (MgSO ₄ ) and evaporated to afford the title compound (yield 46 g). Sample 59 is recrystallized from isopropane (yield 2.5 g, melting point 93-95 ° C.)

Elemental Analysis (%) for C ₉ H ₇ NO ₃ .

Found: C: 61.2, H: 4.1, N: 7.9

Calculation: C: 61.0, H: 4.0, N: 7.9

(C) 2-bromomethyl-5-nitrobenzofuran

N-bromosuccinimide (1.1 g, 6.2 mmol) was added to a solution of 2-methyl-5-nitrobenzofuran (1.09,5.6 mmol) and benzoyl peroxide (50 ml) in carbon tetrachloride (50 ml) and the reaction mixture was brightened. Heat at reflux for 6 hours in the presence of light. The reaction mixture is then cooled, filtered and the filtrate is evaporated to dryness. The residue is recrystallized from petroleum ether to give the title compound (yield 0 75 g, melting point 96-98).

Elemental Analysis for C ₉ H ₆ Br NO ₃ (%)

Found: C: 41.7, H: 2.4, N: 5.3

Calculated value: C: 422, H: 2.4, N: 5.5.

(D) N-methyl-N- (5-nitrobenzofur-2-ylmethyl) -4-nitrofeethylamine

N-ethyl-4-nitrophenethylamine (0.41 g, 2.3 mmol), 2-bromomethyl-5-nitrobenzofuran (0.66 g, 2.6 mmol), sodium iodide (0.39 g, 2.6 mmol) and potassium carbonate (0.36 g, 2.6 mmol) is heated for 8 days at reflux in acetonitrile (50 ml). The solvent is then evaporated, water is added and the mixture is extracted three times with methylene chloride. The combined organic extracts are washed with water, dried (MgSO ₄ ) and evaporated to give a semi-solid and recrystallized from isopropanol to give the title compound (yield 380 mg).

¹ HN.mr (DMSO / TFA): δ = 8.75 (s, 1H); 8.3 (d, 1H); 8.2 (d, 2H); 7.9 (d, 1 H); 7.6 (d, 2H); 7.45 (s, 1 H); 4.75 (t, 2H); 3.2 (t, 2H); 2.9 (s, 2H); 2.5 (s, 3H)

Preparation Example 6

(A) 2-bromomethyl-6-nitbobenzofuran

N-bromosuccineide ("NBS") (1.11 g, 6.2 mmol) was added to 2-medyl-6-nitrobenzomuran (1.009,5.65 phenol) and azobis isobutyronitrile (20 mg) in carbon tetrachloride. The solution is added and the mixture is heated at reflux for 1 l / 2 hours in the presence of bright light. The solvent is then evaporated and the residue is dissolved in methylene chloride, washed with water, dried (MgSO ₄ ), evaporated to dryness and purified by column chromatography on silica eluting with ethylene clavrate / hexane (7: 3). Fractions containing product product were combined and evaporated to yield the title compound (yield 1.43 g). In ¹ HN.Mr, the product clearly showed 20% 2-diboromoethyl-6-nitrobenzofuran, but this was removed. Need not be and the product can be used directly without further purification.

(B) N-methyl-N- (6-nitrobenzoxazin-2-ylmethyl) -4-nitrophenethylamine

N-methyl-4-nitrophenethyla cotton (0.84 g.4.7 mmol). 2-bromomethyl-6-nitrobenzofuran (1.2 g, 4.7 mmol), natio iodide (0.7 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) in acetonitrile at reflux for 18 hours. Heat. The cooled reaction mixture is then filtered and the filtrate is evaporated to dryness and purified by chromatography on silica eluting with ethylene chloride / hexanes (1: 1) followed by methyleneclalide / ethanol (19: 1). Fractions containing product are combined and evaporated and the residue is solidified by treating with decolorized charcoal in ethanol to leave an oil to stand. Recrystallization of the solid from ethanol / methylene chloride affords the title compound (yield 0.7 g, melting point 69-69.5 °).

Elemental Analysis for C ₁₈ H ₁₇ N ₃ O ₅ (%)

Found: C: 60.8, H: 4.8, N: 11.8

Calculation: C: 60.8, H: 4.8, N: 11.8

¹ Hn.mr (CDCl 3): δ = 8.3 (s, 1H); 8.15 (dd, 1 H); 8.1 (d, 2H); 7.55 (d, 1 H); 7.35 (d, 2 H); 6.65 (s, 1 H); 3.8 (s, 2 H); 2.95 (t, 3 H); 2.75 (t, 3H); 2.4 (s, 3 H).

Production Example 7

(A) 2-hydroxymethyl-3-methyl-5-nitrobenzofuran

1 mole diborane in tetrahydrofuran (18 0 ml, 18.0 mmol) is added to a suspension of 3-nedine-5-nitrobenzofuran-2-carboxylic acid (1.1 g, 5 mmol) in tetrahydrofuran at 0 ° C. Stirring is continued for 0 to 30 minutes followed by 18 hours at room temperature and when diborane (50 ml) is added in two portions the reaction mixture is subjected to ultrasound for 2 to 5 hours. Careful then add methanol to the reaction mixture and evaporate off the solvent. The residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, dried (MgSO ₄ ) and purified by column chromatography on silica eluting off the solvent in vacuo and eluting with methylene chloride. Fractions containing product were combined and evaporated to yield the title compound (yield 0.96 g), and the sample was recrystallized from ethyl acetate (melting point 149-150 ° C.).

Elemental Analysis for C ₁₀ H ₉ NO ₄ (%)

Found: C: 57.9, H: 4.2, N: 6.7

Calculated Value: C: 58.0, H: 4.4, N: 6.8.

(B) 2-chloromethyl-3-methyl-5-nitrobenzofuran

Thionylchloride (1.48 g, 12.4 mmol) is added dropwise to a solution of 2-hydroxyethyl-3-methyl-5-nitrobenzofuran (0.86 g, 4.15 mmol) in ethylene chloride (10 ml) and pyridine (2 drops) and the mixture Stir at room temperature for 24 hours. The reaction mixture is then diluted with water, the organic phase is separated and the aqueous phase is reextracted with methylene chloride. The combined organic phases are washed with aqueous sodium bicarbonate solution, dried over Na ₂ SO ₄ and the solvent is evaporated to give the title compound (0.93 g). ). The fraction is recrystallized from ethanol (melting point 141 to 142 °).

Elemental Analysis for C ₁₀ H ₈ ClNO ₃ (%)

Found: C: 52.95, H: 3.7, N: 6.0

Calculated Value: C: 53.2, H: 3.6, N: 6.2

Production Example 8

N-methyl-N- (6-nitroquinol-2-ylethyl) -4-nitrophenethylamine

N-methyl-4-nitrophenethylamine (0.39 g, 215 mmol) and 2-chloromethyl-6-nitroquinoline (0.40 g, 2.1 mmol) are heated in reflux at ethanol (30 ml) for 6 hours. The solvent is then evaporated and the residue is distilled with 2M hydrochloric acid and extracted with methylene chloride. The aqueous layer is basified with aqueous sodium carbonate solution (up to pH-12) and extracted three times with ethylene chloride. The latter organic extract is mixed, dried (MgSO ₄ ) and evaporated to column chromatography on silica eluting with methylene chloride containing ethanol (0% to 1%). Fractions containing product were combined and evaporated to give a solid which was recrystallized from ethanol to give the title compound (yield 0.21 g, melting point 104-105).

Elemental Analysis for C ₁₉ H ₁₈ N ₄ O ₄ (%)

Found: C: 62.4, H: 4.7, N: 15.2

Calculated Value: C: 62.3, H: 4.95, N: 15.3

¹ Hn. Mr (CDCl 3): δ = 8.9 (d, 1H); 8.5 (dd, 1 H); 8.3-8.1 (m, 3 H); 7.6 (d, 1 H); 7.35 (d, 1 H); 3.95 (s, 2 H); 3.0 (t, 2H); 2.8 (t, 2H); 2.4 (s, 3H)

Production Example 9

(A) 4-methanesulfonamidofenethyl mesylate

Methanesulfonyl chloride (146.69, 1.28 moles) is added to a solution of 4-aminophenepil alcohol (82.3 g, 0.6 moles) in pyridone (700 ml) and the mixture is stirred at room temperature for 18 hours. The reaction mixture is then poured into water (700 ml) and the precipitate is collected by filtration, washed with water, dried and recrystallized from ethyl acetate to give the title compound (yield 319, melting point 134 to 136). More 14.5 g of seed product are obtained.

(B) N-benzyl-N-ethyl-4-methanesulfonamidophenethylamine

4-methanesulfonidefenethyl mesylate (10 g, 34 mmol) and N-ethylbenzylamine (10 ml, 67 mmol) are heated at reflux in ethanol (80 ml) for 3 hours. The solvent is evaporated and the residue is taken up in 2M hydrochloric acid and washed twice with methylene chloride. The aqueous layer is basified with aqueous sodium bicarbonate solution (up to PH-12) and extracted with methylene chloride. The latter organic extract is dried (MgSO _{4) and} evaporated to give an oil which solidifies upon grinding with diisopropyl ether. The solid was filtered off, decanted and the filtrate was evaporated in vacuo to yield the title compound as an oil (yield 4.4 g).

¹ HN.mr (CDCl 3): δ = 7.2 (s, 5H); 7.05 (s, 4H); 3.6 (s, 2H); 2.95 (s, 3 H); 2.70 (s, 4 H); 2.40 (q, 2 H); 1.1 (t, 3 H).

(C) N-ethyl-4-methanesulfonamidophenethylamine

N-benzyl-N-ethyl-4-methanesulfonamidophenethylamine (43 g, 12.9 mmol) in ethanol (50 ml) containing 10% Pd / c (0.5 g) under hydrogen atmosphere (50 psi = 344.7 kPa) Stir for 5 hours. The mixture is then filtered, evaporated and the residue is triturated with ether to give the title compound (yield 2.6 g, melting point 125-128 °).

N.m.r. (CDCl 3 / DMSO): δ = 7.06 (s, 4H); 4.9 (s, 2H); 2.86 (s, 2 H); 2.8 (s, 2 H); 2.65 (q. 2 H); 1.05 (t, 3 H).

Production Example 10

(A) N-methyl-N- (3-methyl-5-nitrobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

N-ethyl-4-epansulfonamidophenethylamine (1.669,7.3 mmol) and 2-chloroethyl-3-methyl-5-nitrobenzofuran (see Preparation Example 7B-0.829,3.6 mmol) were added to ethanol (20 ml). Heating at reflux for 3 hours. The solvent is then evaporated and the residue is purified by kip chromatography on silica eluting with ethylene chloride / hexane (4: 1) followed by methylene chloride containing methanol (0% to 5%). Fractions containing product are combined and evaporated and the residue is recrystallized from ethanol to give the title compound (yield 1.52 g, melting point 124-124.5).

Elemental Analysis for C ₂₀ H ₂₃ N ₃ O ₅ S (%):

¹ Hn. Mr (CDCl 3): δ = 8.45 (d, 1H); 8.25 (dd, 1 H); 7.5 (d, 1 H); 7.2 (q, 4H); 3.8 (s, 2 H); 3.05 (s, 3H); 2.9 (t, 2H); 2.75 (t, 2H); 2.4 (s, 3H); 2.35 (s, 3 H).

Found:. C: 57.7, H: 5.65, N: 10.0

Calculation: C: 57.5, H: 5.55, N: 10.1

¹ Hn. Mr (CDCl 3): δ = 8.45 (d, 1H); 8.25 (dd, 1 H); 7.5 (d, 1H); 7.2 (q, 4H); 3.8 (s, 2 H); 3.05 (s, 3 H); 2.9 (t, 2H); 2.75 (t, 2 H); 2.4 (s, 3 H); 2.35 (s, 3 H).

(B) N-methyl-N- (3-methyl-5-inobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

Catalytically hydrogenated the product of part (A) (0,7 g) to yield the title compound (yield 0.65 g) for 4 hours reaction time similarly to 1 (c).

¹ HN. Mr (CD3OD): δ = 7.25 (m, 6H); 6.9 (d, 1 H); 6.8 (dd, 1 H); 3.8 (s, 2 H); 2.95 (s, 3 H); 2.9 (m, 2H); 2.7 (m, 2 H); 2.4 (s, 3H); 2.35 (s, 3H)

Production Example 11

(A) N-ethyl-N- (6-nitroquinol-2-ylmethyl) -4methane-sulfonamidophenethylamine

N-ethyl-4-methanesulfonamidophenethylamine (see Preparation Example 9 (C) -1.7 g, 7.0 mmol) and 2-clobomethyl-6-nitroquinoline (0.78 g, 4.1 mmol) were prepared using ethanol ( 50 ml) at reflux for 4 hours. The solvent is then evaporated and the residue is diluted with aqueous sodium bicarbonate solution and extracted with ethylene chloride. The organic layer is dried (MgSO ₄ ), evaporated and the residue is purified by column chromatography on silica eluting with methylene chloride. Fractions containing product are combined and evaporated to afford the title compound as an oil (yield 0.569).

¹ HN.mr (CDCl 3): δ = 8.6 (d, 1H); 8.3-8.0 (m, 2 H); 7.6 (d, 1 H); 7.1 (s, 1 H); 7.0 (s, 4H); 3.9 (s, 2H); 2.9 (s, 2H); 2.7 (s, 2H); 2.65 (q, 2 H); 1.05 (t, 3H)

(B) N-ethyl-N- (6-aminoquinol-2-ylmethyl) -4-methanesulfoniado-phenethylamen

The product of part (A) (0.55 g) was catalytically hydrogenated for 3 hours at 15 p.si (103.4 kPa) by passing H ₂ through 5% Pd of C phase in ethyl acetate, similarly to Preparation Example 1 (C) The title compound is obtained (0.51 g).

¹ HN.mr (CDCl 3): δ = 7.7 (d, 1H); 7.5 (d, 1 H); 7.15 (d, 1 H); 6.9 (broad s, 5H); 6.65 (d, 1 H); 3.75 (s, 2 H); 2.95 (s, 3 H); 2.6 (s, 4H); 2.5 (q, 2H); 0.95 (t, 3 H).

Preparation Example 12

(A) 6-amino-2-methylquinoline

2-ethyl-6-nitroquinoline (18.8 g) is stirred for 2 h at 30 p.s.i (equivalent to 206.8 kPa) in an ethanol solution containing 5% Pd / c under hydrogen atmosphere. The catalyst is then removed by filtration, the filtrate is evaporated in vacuo to a small volume, the resulting precipitate is collected by filtration, washed with ethanol and ether and dried to give the title compound (yield 13.29, melting point l88 to). l89。).

Elemental Analysis for C ₁₀ H ₁₀ N ₂ (%):

Found: C: 75.7, H: 6.4, N: 17.6

Calculated Value: C: 75.9, H: 6.4, N: 17.7

(B) 6-edansulfonamido-2-methylquinoline

Methanesulfonylchloride (6.2 ml) is added to a stirred solution of 6-amino-2-ethylquinoline (12.5 g) in pyridine (100 ml) cooled to 5 ° C. Stirring is continued for 17 hours at room temperature. The pyridine is then removed by evaporation in vacuo, the residue is diluted with aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined organic extracts are mixed, dried (MgSO ₄ ) and evaporated in vacuo to afford the title compound (yield 13.09, melting point 151 to 153 °).

Elemental Analysis for C ₁₁ H ₁₂ N ₂ O ₂ S (%):

Found: C: 55.4 H: 5.2, N: 11.6

Calculated Value: C: 55.9 H: 5.1, N: 11.9

(C) 6-methanesulfonamido-2-methylquinoline-1-oxide

m-chloroperbenzoic acid ("MCPBA") (5.2 g) is added in part to a solution of 6-methanesulfonamido-2-methyl-quinoline (6 g) in methylene chloride and stirring is continued for 17 hours. The reaction mixture is then diluted with aqueous sodium bicarbonate solution and the organic layer is separated. The aqueous layer is extracted with methylene chloride. The combined organic layers are washed with aqueous sodium bicarbonate solution, dried (MgSO ₄ ) and evaporated in vacuo to give a solid which is recrystallized from ethanol to give the title compound (yield 1.6 g, melting point 241 to 243 ° C.).

Elemental Analysis for C ₁₁ H ₁₂ N ₂ O ₃ S (%):

Found: C: 525, H: 4.95, N: 11.0

Calculation: C: 524, H: 48, N: 11.1

(D) 2-chloromethyl-6-methanesulfonamidoquinoline

6-Methanesulfonamido-2-methylquilin-1-oxide (1.65 g) and -toluenesulfonyl chloride (1.72 g) were heated in a 1,2-dichloroethane solution at reflux for 1 hour and then reaction The mixture is left at room temperature for 17 hours. The reaction mixture is washed twice with aqueous sodium bicarbonate solution, dried (MgSO ₄ ) and evaporated in vacuo. The residue is purified by capsule chromatography on silica eluting with ethylene chloride containing ethanol (0% to 1%). Fractions containing the product are combined and evaporated to give a rubber which solidifies upon grinding with ether. Recrystallization from toluene affords the title compound (yield 0.75 g, melting point 160-162 °).

Elemental analysis of% C ₁₁ H ₁₁ N ₂ O ₂ ClS.

Found: C, 49.3, H: 39, N: 10.1

Calculation: C, 48.8, H: 41, N: 10.35

(A) 2-chloromethyl-5-nitrobenzo [b] thiophene

Thionyl chloride (1.0 ml) is added dropwise to a stirred mixture of 5-nitrobenzo [b] thiophen-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml). The solution is stirred at room temperature for 4 hours and then washed with water and then with aqueous sodium bicarbonate solution and dried (Na ₂ SO ₄ ). The solvent is evaporated and the residue is chromatographed on silica gel. Elution with dichloromethane gives a solid which is crystallized from ethyl acetate to give the title compound (yield 0.73 g, melting point 110-112 °), which is used directly in the next step.

(B) N-methyl-N- [5-nitro-2-benzo [b] thienylmethyl] -4-nitrophenethylamine

The mixture of product (3.20 g), N-methyl-4-nitropenylamine (2.25 g), potassium carbonate anhydride (4.0 g) and acetonitrile (40 ml) of the above-mentioned part (A) was refluxed and stirred for 20 hours. Heat, then cool and filter. The residue is washed with acetonitrile, the filtrates are combined and the washes are evaporated to give an oil which is chromatographed on silica gel. Elution first with dichloromethane affords impurities followed by pure product. Fractions containing product were evaporated to yield the title compound [yield 4.17 g, melting point 76-78 ° (from isopropanol)].

Elemental Analysis for C ₁₈ H ₁₇ N ₃ O ₄ S (%):

Found: C; 57.8, H; 4.4, N: 11.1

Calculated Value: C; 58.2, H; 4.6, N; 11.3

(C) N-methyl-N- [5-amino-2-benzo [b] thienylmethyl] -4-aminophenethylamine

The mixture of (B) product (1.0 g) and tin chloride dihydrate (6.07 g) in ethanol (100 ml) is heated under reflux for 8 hours and then evaporated. An excess of 20% aqueous sodium hydroxide solution is added and the mixture is extracted with dichloromethane. The combined organic extracts are washed with water, dried (Na ₂ SO ₄ ) and evaporated to give an oil which is chromatographed on silica cells. Eluting with dichloromethane / methanol (99: 1) to afford impurities, then collecting the appropriate fractions and evaporating and then further eluting with dichloromethane / ethanol (98.2) to give the product as an oil (0.30 g) which is Example 6 Use immediately in the way.

[Production Example l4]

(A) 4- [2- (methanesulfonyloxy) ethyl] -methanesulfonanilide

Methanesulfonyl chydride (50 ml) is added dropwise to a stirred solution of 4-aminophenethylalcohol (41.159) in pyridine (350 ml) at 0 ° C. over 0.5 h. Warm the mixture to room temperature and stir overnight. The mixture is then poured into water (700 ml) to give an orange solid crystal. After filtration, the solid is dissolved in methylene chloride, dried over magnesium sulfate, filtered and the filtrate is evaporated again. Crystallization of the resulting solid from ethyl acetate affords the title compound (yield 45.5 g, melting point 136-137 °).

Elemental Analysis for C ₁₀ H ₁₅ NO ₅ S ₂ (%):

Found: C: 40.6, H: 5.2, N: 4.9

Calculated Value: C: 40.9, H: 5.15, N: 4.8

(B) 4- [2- (ethylamino) ethane] methanesulfonanilide.

To a solution of 4- [2- (methanesulfonyloxy) ethyl] methanesulfonanilide (10.3 g) in ethanol (20 ml) is added an industrially methylated alcohol (33% solution 30 ml) methylamine solution. The mixture is heated for 17 h with stirring in a pressure vessel at 85 ° C. After cooling, the resulting solution is evaporated to dryness, the residue is dissolved in water and the resulting solution is basified by addition of sodium hydroxide (1.4 g) in water (12 ml). Evaporation yields an off-white solid and is chromatographed on silica eluting with methylene chloride / methanol (3: 1) (“kieselgel 60” ™). Collect the appropriate fractions and evaporate to give a white solid (4.8 g) which is crystallized from ethyl acetate / methanol to give the title compound (yield 1.8 g, melting point 133-135 °).

Elemental Analysis (%) for C ₁₀ H ₁₆ N ₂ O ₂ S.

Found: C; 52.5, H: 7.1, N: 12.2

Calculated Value: C; 52.6, H: 7.1, N: 12.3

Claims (7)

A compound of formula (A) or a salt thereof

Wherein R is —NHSO ₂ (C ₁ to C ₄ alkyl), —NH ₂ or —NO ₂ , R ¹ is C ₁ to C ₄ alkyl and “Het” is a group.

[Wherein R ² is H, CH ₃ or C ₂ H ₅ ; R ³ is —NHSO ₂ (C ₁ to C ₄ alkyl), —NH ₂ or —NO ₂ ; X is O, S or NR ₄ , wherein R ⁴ is H or CH ₃ ] provided that when one of R and R ³ is —NO ₂ , the other is not —NH ₂ . The compound or pharmaceutically acceptable salt thereof of claim 1, wherein R is -NHSO ₂ (C ₁ to C ₄ alkyl) and R ³ is -NHSO ₂ (C ₁ to C ₄ alkyl). The compound of claim 2, wherein R is —NHSO ₂ CH ₃ , R ¹ is CH ₃ or C ₂ H ₅ , and “Het” is a group

Wherein R ² is H or CH ₃ , X is O or S, and R ³ bonded at position a or b of “Het” is —NHSO ₂ CH ₃ . The compound of claim 3 having the structure

A pharmaceutical composition useful as an antiarrhythmic agent, comprising the compound claimed in any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. Use of a compound as claimed in any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the prophylaxis or plaque of deep arrhythmias. The compound of claim 3 having the structure