KR960005793B1 - Anti-arrhythmic agents - Google Patents

Abstract

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Description

Arrhythmia Medicine

The present invention relates to certain sulfonamides and intermediates thereof, which are therapeutic agents for arrhythmia. The arrhythmic therapeutically active compounds of the invention can increase the nonresponsiveness to premature stimulation by prolonging the duration of action potentials in myocardium and conductive tissue. Thus, they are a class III arrhythmia treatment according to Vaughan Williams (Anti-Arrhythmic Action, E. M., Academic Press, 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 a wide range of ventricular and lossy arrhythmias including atrial and atrial fibrillation. Since they do not change the rate at which the impulse conducts, they have a weaker property of promoting or weakening arrhythmia than conventional drugs (mostly I-series), and also have fewer neurological side effects. Some compounds also have positive inotropic activity, which is particularly beneficial for patients with impaired pump function of the heart.

Accordingly, the present invention provides compounds of the general formula (A) and salts thereof.

Wherein R ^a is —NO ₂ , —NH ₂ or —NHSO ₂ R ¹ , wherein R ¹ is a C ₁ -C ₄ alkyl group and R ^b is —NO ₂ , —NH ₂ or R ³ [Wherein R ³ is —NHSO ₂ (C ₁ -C ₄ alkyl) or -CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently H or C ₁ -C ₄ alkyl or nitrogen to which they are attached Together with the atom represents a 1-pyrrolidinyl, piperidino, morpholino or N-methylpiperazin-1-yl group), provided that if one of R ^a and R ^b -NO ₂ is Is not —NH ₂ , X is O, S or a direct bond, Y is an ethylene group unsubstituted or substituted by a methyl group, and “alk” is ethylene, trimethylene or unsubstituted or substituted by a methyl group Tetramethylene group, R is C ₁ -C ₄ alkyl and R ² is H, halo, CF ₃ or C ₁ -C ₄ alkyl.

Formula (A) includes arrhythmia therapeutic compounds, and synthetic intermediate compounds useful in the preparation of these arrhythmia therapeutics.

These compounds having arrhythmic therapeutic activity are compounds of the general formula (I) below. The remaining compounds are only synthetic intermediates.

The present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, which are useful as therapeutic agents for arrhythmias.

Wherein R and R ¹ are each independently C ₁ -C ₄ alkyl, X is O, S or a direct bond, Y is an ethylene group unsubstituted or optionally substituted by a methyl group, and “alk” is non- Ethylene, trimethylene and tetramethylene groups, substituted or substituted by a methyl group, R ² is H, halo, CF ₃ or C ₁ -C ₄ alkyl, and R ³ is of the formula —NHSO ₂ (C ₁ -C ₄ Alkyl) or -CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently H or C ₁ -C ₄ alkyl or together with the nitrogen atom to which they are attached 1-pyrrolidinyl, piperidino, morpholino Or an N-methylpiperazin-1-yl group).

"Halo" is F, Cl, Br or I and the C ₃ and C ₄ alkyl groups can be straight or branched.

R is preferably CH ₃ or C ₂ H ₅ , most preferably CH ₃ . R ¹ is preferably CH ₃ . Examples of "alk" are-(CH ₂ ) _n- , where n is 2, 3 or 4. -CH (CH ₃ ) CH _2- , -CH ₂ CH (CH ₃ )-, -CH (CH ₃ ) CH ₂ CH _2-, and -CH ₂ CH ₂ CH (CH ₃ )-and the like. "Alk" is preferably-(CH ₂ ) _n- , where n is 2, 3 or 4. -CH (CH ₃ ) CH ₂ -or -CH ₂ CH (CH ₃ )-.

또는 -NHSO₂CH₃이다. R³는 가장 바람직하게는 -NHSO₂CH₃이다."Alk" is most preferably-(CH ₂ ) _2- . X is preferably O. Y is preferably-(CH ₂ ) _2- . R ² is preferably H, CH ₃ or Cl. R ² is most preferably H. R ³ is preferably -CONH ₂ , -CONHCH ₃ , -CON (C ₂ H ₅ ) ₂ ,

Or -NHSO ₂ CH ₃ . R ³ is most preferably -NHSO ₂ CH ₃ .

One of the preferred compounds of formula (I) is those in which R, R ¹ , R ² , R ³ and "alk" are as defined in formula (I) above, Y is-(CH ₂ ) ₂ -and X is O, or S. Further preferred compounds of formula (I) are those in which R, R ¹ , R ² , R ³ and "alk" are as defined in formula (I) above, X is a direct bond and Y is-(CH ₂ ) ₂ -phosphorus compound.

Preferred compounds each have the following structural formula:

먼저 언급된 화합물이 가장 바람직하다.

Most preferred are the compounds mentioned first.

Pharmaceutically vanished salts of compounds of formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, Acid addition salts formed from acids forming non-toxic acid addition salts containing pharmaceutically acceptable anions such as citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate salts . These compounds also form metal salts, for example alkaline earth metals and alkali metal salts. Most preferred are sodium and potassium salts. These salts can be prepared by conventional methods.

To assess the effect of the compound on the atrial nonresponsiveness, the right atrium half of the guinea pig is placed in a bath containing physiological saline solution and one end is connected to a force transducer. A field electrode is used to stimulate tissue at 1 Hz. After every eighth basic stimulus (S ₁ ), an early stimulus (S ₂ ) is triggered to determine the effective duration of response (ERP). When passing the S ₂ is the propagation reaction by regenerative S ₁ S ₂ coupling interval is gradually increased up to. This is defined as ERP. Then determine the concentration of compound (ED ₂₅ ) needed to increase ERP by 25%. ERP is also measured in the right papillary muscle of guinea pigs cultured in physiological salt solution. A bipolar electrode is used to stimulate the muscle at one end and record the electrical conductivity propagated at the opposite end through the monopolar surface electrode. ERP is determined as above using the extrastimulus technique. The distance between the irritating artefact and the peak of the electrical diagram is measured to obtain the transit time from the digital storage oscilloscope (ie the time required for the shock to be transmitted in the longitudinal direction of the muscle).

Atrial and ventricular ERP are also measured in conscious dogs with respiratory discontinuation or consciousness while the atrium or right ventricle is at a constant rate.

Compounds of formula (I) may be administered alone, but are generally administered in a mixture with a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. They can also be administered prophylactically to patients with arrhythmias and patients who may have arrhythmias. For example, the compounds may be in the form of tablets containing excipients, such as starch of lactose, alone in capsules or in mixtures of capsules and excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. It can be administered orally. The compound can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, it is best to use the compound parenterally, for example in the form of a sterile aqueous solution which may contain sufficient salt or glucose to make the solution isotonic.

Formula (I) compounds, usually for adult patients (70 kg body weight), for administration to persons in the healing or prophylactic treatment of heart conditions such as ventricular and ventricular arrhythmias including atrial and ventricular fibrillation. Oral dosage of is preferably administered divided into four or more times per day in the range of 1 to 75mg. Intravenous dosages are preferably in the range of 0.5 to 10 mg per single dose. Severe cardiac arrhythmias are preferably treated with intravenous administration so as to quickly convert to normal rhythm. Thus, single tablets or capsules for typical adult patients may contain, for example, 1 to 25 mg of active compound in a pharmaceutically acceptable suitable vehicle or carrier. It will be determined by the attending physician and can be modified according to the weight and condition of the patient being treated.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof as described above, together with a pharmaceutically acceptable diluent or carrier.

The invention also provides a method of preventing or treating cardiac arrhythmias comprising administering to a cardiac arrhythmia patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. do.

In addition, the present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament, in particular as a therapeutic agent for arrhythmia.

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

Route I

Compounds of formula (I) may be prepared by the following general routes, wherein R, R ¹ , R ² , R ³ , alk, X and Y are as described above in formula (I) above. Starting from compounds in which R ^a is -NH ₂ :

The reaction is generally carried out in a suitable organic solvent at room temperature, optionally in the presence of a base (acid acceptor) such as pyridine, triethylamine, sodium bicarbonate or potassium carbonate. The presence of the acid acceptor is particularly useful when alkanesulfonyl chloride or bromide is used as the acylating agent. As the sulfonylating agent, it is preferable to use sulfonic anhydride (R ¹ SO ₂ ) ₂ O in methylene chloride or sulfonyl chloride R ¹ SO ₂ Cl in pyridine. Product (I) can then be separated and purified by conventional methods.

Route II

In case R ³ is —NHSO ₂ (C ₁ -C ₄ alkyl), the following route starting from an intermediate in which R ^a and R ^b is —NH ₂ is particularly useful:

R, R ² , X, Y and "alk" are as defined in the general formula (I) above.

The reaction can be carried out similarly to route I even if at least two equivalents of sulfonylating agent should be used, and in the final product (IA), each alkylsulfonamide group will be identical.

Route III

When R ³ is -NHSO ₂ (C ₁ -C ₄ alkyl), the following route starting from the compound where R ^b is -NH ₂ can also be used:

R, R ¹ , R ² , X, Y and "alk" are as defined in the general formula (I) above.

The reaction can be carried out again similar to route I. This route can obviously be used to prepare end products that differ in alkanesulfonamido substituents.

The novel intermediates used in routes I to III are also part of the present invention, which include compounds of formula (A) as defined above wherein at least one of R ^a and R ^b is nitro or amino.

Starting materials for this route can be obtained by the conventional methods illustrated below.

(d) for intermediates where X is only O or S:

[X = only O or S, S]

In variations of this route, thiophenols or phenols in which R ³ is nitro may be used. The hydrogenation step can also reduce this nitro group to an amino group (as in route (C) above), thus producing an intermediate of formula (III) wherein X is S or O.

Further variations of this route useful for the preparation of certain compounds of formula (IIA) wherein the "alk" is -CH (CH ₃ ) CH ₂ -or -CH ₂ CH (CH ₃ )-are as follows:

Mixtures of 2-nitro containing compounds are considered to be the result of competitive ring opening of intermediate aziridinium cations formed during the reaction. Nitro-containing intermediates may be separated by chromatography prior to the catalytic hydrogenation step.

If the starting materials used in (a) to (g) above are not known compounds, they can be prepared again by the usual methods exemplified below:

Route IV

Compounds of formula (I) can also be prepared by the following methods:

Wherein R, R ¹ , R ² , R ³ , X, Y and alk are as described above in formula (I) above, Q is chloro, bromo, iodine, C ₁ -C ₄ alkanesulfonyl Leaving groups such as oxy (particularly methanesulfonyloxy), benzenesulfonyloxy or toluenesulfonyloxy.

The presence of acid acceptors, such as sodium bicarbonate, triethylamine or calcium carbonate, is optional, but preferred when Q is halo.

The reaction is carried out in an organic solvent (eg ethanol), at reflux temperature, generally below about 120 ° C. The reaction is preferably carried out under reflux. The product can then be separated and purified by conventional methods.

Starting materials can again be obtained conventionally.

When the compound of formula (I) contains one or more optically active centers, the present invention includes both divided and undivided forms.

In the following examples all temperatures are in degrees Celsius, illustrating the preparation of compounds of formula (I). In these examples, the three atmospheres are equal to 3.04 × 10 ⁵ Pa and 50 p.si to 3.45 × 10 ⁵ Pa.

Example 1

(A) 4- {2- [N-methyl-N- (4-nitrophenethyl) amino] ethoxy) benzamide

N-methyl-4-nitrophenethylamine (1.8 g) in acetonitrile (100 mL) [JoC, (1956), 21, 45] and 4- (2-chloroethoxy) benzamide (see Preparation Example 12) To the solution is added potassium carbonate (3.0 g) and sodium iodide (1.5 g) and the suspension is stirred at reflux for 72 hours. After evaporation, 2N aqueous sodium bicarbonate solution is added to the oily solid residue and extracted three times with methylene chloride. The combined organic layers are washed with saturated aqueous saline solution, dried over magnesium sulfate, filtered and evaporated to give a yellow oil.

The oil is ground with diisopropyl ether to give 2.3 g of a yellow solid. It is recrystallized from toluene to give the title compound (1.4 g) having a melting point of 116 to 118 ° C. which is used directly without further purification.

(B) 4- {2- [N- (4-aminophenethyl) -N-methylamino] ethoxy} benzamide

A 4- {2- [N-methyl-N- (4-nitrophenethyl) amino] ethoxy} benzamide (1.4 g) solution in ethanol (100 mL) was present in the presence of Ranickel (trade name, "Nicat 102"). Under 3 hydrogen pressure at room temperature for 16 hours. The reaction mixture was filtered and evaporated to dryness to yield a yellow solid (1.2 g) which was crystallized from ethyl acetate to give the title compound (1.1 g) having a melting point of 110 to 112 ° C.

Elemental Analysis%: C ₁₈ H ₂₃ N ₃ O ₂

Found; C, 69.1; H, 7.3; N, 13.05;

Calculated value; C, 69.0; H, 7.4; N, 13.4.

(C) 4- {2- [N-methyl-N- (4-methanesulfonamidophenethyl) amino] ethoxy} benzamide

A solution of 4- {2- [N- (4-aminophenethyl) -N-methylamino] ethoxy} benzamide (1.0 g) and methanesulfonic anhydride in anhydrous methylene chloride (50 mL) for 16 hours at room temperature Stir. After evaporation, 2N aqueous sodium bicarbonate solution was added to the residue, followed by extraction three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered and evaporated to give a light brown solid. Recrystallization from toluene / ethyl acetate yields the title compound (0.31 g) with a melting point of 147 ° C.

Elemental Analysis%: C ₁₉ H ₂₅ N ₃ O ₄ S

Found; C, 58.35 H, 6.7; N, 10.45;

Calculated value; C, 58.3; H, 6.4; N, 10.7.

[Examples 2 to 5]

The following compounds are prepared analogously to examples (A) to (C) of Example 1 from suitable starting materials. In Examples 3 and 5, the product was added ethyl acetate to the solid resulting from the second evaporation step in part (C) and then treated with ethereal hydrogen chloride, and the resulting hydrochloride salt was filtered to ethyl acetate / methanol. Characterized as a hydrochloride salt by recrystallization.

Example 6

(A) N-methyl-4- (2-methylaminoethoxy) benzamide

To a 33% solution of methylamine in industrial methylated spirit (50 mL) was added methyl 4- (2-chloroethoxy) benzoate (4.3 g) (see Preparation Example 11) and the mixture was pressurized to 130 mL. Stir for 16 hours while heating to 100 ° C. in the vessel. After evaporation to dryness, the resulting solid is added to 10 ml of 2N aqueous sodium hydroxide solution and extracted three times with methylene chloride. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and evaporated to give a colorless solid. Crystallization from isopropanol affords the title compound (2.1 g) with a melting point of 95-96 ° C.

Elemental Analysis%: C ₁₁ H ₁₆ N ₂ O ₂

Found; C, 63.7; H, 7.6; N, 13.4;

Calculated value; C, 63.4; H, 7.7; N, 13.45.

(B) N-methyl-4- {2- [N'-methyl-N '-(4-nitrophenethyl) amino] ethoxy} benzamide

To a solution of N-methyl-4- (2-methylaminoethoxy) benzamide and 4-nitropenethyl bromide in acetonitrile (100 mL) was added potassium carbonate (3.0 g) and sodium iodide (1.5 g) and the suspension was refluxed. Stir for 72 hours. After evaporation, 2N aqueous sodium hydroxide solution is added and then extracted three times with methylene chloride. The combined organic layers are washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered to give evaporated yellow oil. The oil is triturated with diisopropylether to give the title compound as a yellow solid (2.4 g) which is used without further purification.

Nmr (CDCl ₃ ), ppm, δ = 7.9 (d, 2H); 7.52 (d, 2 H); 7.12 (d, 2 H); 6.63 (d, 2 H); 3.9 (t, 2 H); 2.8 (m, 9 H); 2.28 (s, 3 H).

(C) N-methyl-4- {2- [N '-(4-aminophenethyl) -N'-methylamino] ethoxy} benzamide

A solution of N-methyl-4- {2- [N'-methyl-N '-(4-nitrophenethyl) amino] ethoxy} benzamide (2.3 g) in ethanol (100 mL) was added to Raney Nickel (" In the presence of Nicat 102 "), the mixture is stirred for 16 hours at room temperature under 3 hydrogen pressure. The reaction mixture is filtered and evaporated to dryness to give yellow oil (2.1 g). Elution with ethyl acetate and chromatography on silica (trade name "Kieselgel 60") give the title compound as a colorless oil (1.7 g) which is used directly without further purification.

Nmr (CDCl ₃ ), ppm, δ = 7.72 (d, 2H); 7.0 (d, 2H); 6.92 (d, 2 H); 6.62 (d, 2 H); 3.0 (d, 3H); 2.88 (t, 2 H); 2.7 (s, 4 H); 2.42 (s, 3 H).

(D) N-methyl-4- {2- [N '-(4-methanesulfonamidophenethyl) -N'-methylamino] ethoxy} benzamide hydrochloride

N-methyl-4- {2- [N '-(4-aminophenethyl) -N'-methylamino] ethoxy) benzamide (1.6 g) and methanesulfonic anhydride (0.87) in anhydrous methylene chloride (50 mL) g) The solution is stirred overnight at room temperature. After evaporation, the resulting oily solid is treated with 2N aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined organic layers are washed with saturated aqueous brine solution, dried over magnesium sulfate, filtered and evaporated. Chromatography on silica eluting with ethyl acetate (trade name "Kieselge 160 °") affords a colorless oil (0.52 g), which is dissolved in ethyl acetate and an ethereal solution of hydrogen chloride is added until precipitation is complete. The colorless solid was filtered off and crystallized from ethyl acetate / methanol to give the title compound (0.2 g) with a melting point of 160 ° C.

Elemental Analysis%: C ₂₀ H ₂₇ N ₃ O ₄ SHCl

Found; C, 54.2; H, 6.6; N, 9.25;

Calculated value; C, 54.35; H, 6.4; N, 9.5.

Example 7

(A) 1- (4-nitrophenoxy) -2- [N-methyl-N- (4-natrophenethyl) amino] ethane

N-methyl-4-nitrophenethylamine (1.5 g) in acetonitrile (50 mL) (JoC, [1956], 21, 45) and 2- [4-nitrophenoxy] ethyl chloride (1.55 g) To the solution (CA, [1955], 49, 3163e) was added potassium carbonate (1.25 g) and sodium iodide (1.2 g) and the suspension was stirred at reflux for 72 h. After evaporation to dryness, the oily solid residue is partitioned into 2N aqueous sodium bicarbonate solution and ethyl acetate. After two additional extractions with ethyl acetate, the organic layers are combined, washed with saturated aqueous brine solution, dried over magnesium sulfate, filtered and evaporated. The resulting orange solid (2.7 g) is crystallized from ethanol to give the title compound (1.9 g) having a melting point of 74 ° C.

Elemental Analysis%: C ₁₇ H ₁₉ N ₃ O ₄

Found; C, 58.75; H, 5.4; N, 12.15;

Calculated value; C, 59.1; H, 5.5; N, 12.2.

(B) 1- (4-aminophenoxy) -2- [N- (4-aminophenethyl) -N-methylamino] ethane

A solution of 1- (4-nitrophenoxy) -2- [N-methyl-N- (4-nitrophenethyl) amino] ethane (1.5 g) in ethanol (100 mL) was added to Raney Nickel (trade name, "Nicat 102 Stir for 16 hours at room temperature under 3 hydrogen pressure in the presence of "). The reaction mixture is filtered and evaporated to dryness. The oil residue is redissolved in ether, filtered and evaporated to give a yellow solid (1.1 g). Crystallization from ethyl acetate / 60-80 ° petroleum ether affords the title compound (0.9 g) with a melting point of 73-74 ° C.

Elemental Analysis%: C ₁₇ H ₂₃ N ₃ O

Found; C, 71.3; H, 8.1; N, 14.7;

Calculated value; C, 71.55 H, 8.1; N, 14.7.

(C) 1- (4-methanesulfonamidophenoxy) -2- [N- (4-methanesulfonamidophenethyl) -N-methylamino] ethane

A solution of 1- (4-aminophenoxy) -2- [N- (4-aminophenethyl) -N-methylamino] ethane (0.75 g) and methanesulfonic anhydride (1.0 g) in anhydrous methylene chloride (50 mL) Stir overnight at room temperature. After evaporation, the resulting oil is partitioned into 2N aqueous sodium carbonate solution and ethyl acetate. After two additional extractions with ethyl acetate, the organic layers are combined, dried over magnesium sulfate, filtered and evaporated. The resulting colorless solid (1.2 g) was crystallized from ethyl acetate / methanol to give the title compound (0.6 g) having a melting point of 147 to 149 ° C.

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₅ S ₂

Found; C, 52.1; H, 6. 25; N, 9.45;

Calculated value; C, 51.9; H, 6. 15; N, 9.4.

[Examples 8 to 14]

The following compounds were prepared analogously to the methods of examples (A)-(C) above starting from the corresponding starting materials except using 2- (nitrophenoxy) ethyl bromide rather than chloride in part (A) Then separate in the indicated form. The hydrochloride salt is prepared by dissolving the residue of the final evaporation step in ethyl acetate and adding ethereal hydrogen chloride, then filtering off the precipitate of the resulting hydrochloride salt and then recrystallizing with the indicated solvent.

Starting materials 4- (3-bromopropoxy) nitrobenzene and 4- (4-bromobutoxy) nitrobenzene are described in JACS, (1951), 73, 3159 and CA, 59, 9883, respectively. Described.

Starting materials N-methyl-1- (4-nitrophenyl) -2-propylamine and N-methyl-2- (4-nitrophenyl) -1-propylamine are described in JACS, (1946), 68, 1153.

[Examples 15 and 16]

The following compounds were prepared in corresponding parts of the corresponding starting materials except for using methanesulfonyl chloride in pyridine instead of methanesulfonic anhydride in methylene chloride in part (C). See (C) and (D) of Preparation Example 6. Is prepared similar to the method of parts (B) and (C) of Example 7. In Example 16, the hydrochloride salt is obtained as described in the related description relating to Examples 8-14.

Example 17

(A) 2- [N-methyl-N- (4-nitrophenethyl) amino] ethanol

A mixture of 4-nitrofenethyl bromide (11.5 g) and N-methylethanolamine (8.25 g) in xylene (100 ml) is stirred at reflux for 16 h. After evaporation, the residue is partitioned in 5% aqueous sodium bicarbonate solution and methylene chloride. The organic layer is washed with saturated aqueous brine, dried over MgSO ₄ , filtered and evaporated to give an orange oil (10.1 g). Chromatography on silica eluting with ethyl acetate (trade name "Kieselgel 60") and the appropriate fractions are collected and evaporated to afford the title compound (7.5 g) as a yellow oil. Mmr (CDCl ₃ ) ppm, delta = 8.05 (d, 2H); 7.2 (d, 2H); 3.52 (t, 2 H); 2.61 (m, 6 H), 2.3 (s, 3 H).

(B) 2- [N-methyl-N- (4-nitrophenethyl) amino] ethyl chloride hydrochloride

Thionyl chloride (3 ml) is added dropwise with stirring at 0 ° C. to a solution of 2- [N-methyl-N- (4-nitrophenethyl) amino] ethanol (8.0 g) in anhydrous methylene chloride (75 ml). The mixture is allowed to warm to ambient temperature and stirred for 16 hours. The resulting solid is filtered, washed with anhydrous ether and dried to give a colorless product (7.1 g). Crystallization from ethyl acetate / methanol affords the title compound (6.0 g) with a melting point of 168-169 ° C.

Elemental Analysis%: C ₁₁ H ₁₅ CIN ₂ O ₂ HCl

Found: C, 46.8; H, 5.8; N, 9.85;

Calculated: C, 47.3; H, 5.8; N, 10.0.

(C) 2- [N-methyl-N- (4-nitrophenethyl) amino] -1- (4-nitrophenylthio) ethane

2- [N-methyl-N- (4-nitrophenethyl) amino] ethyl chloride hydrochloride (3.0 g), 4-nitrothiophenol (1.7 g) and potassium carbonate (4.0 g) in acetonitrile (100 ml) Stir at reflux for 16 h. After evaporation, the residue is partitioned in water and ethyl acetate. The organic layer is washed with saturated aqueous brine, dried over MgSO ₄ , filtered and evaporated to give an orange oil (3.6 g). Elution with ethyl acetate, chromatography on silica (trade name "Kieselgel 60"), and the appropriate fractions are collected and evaporated to afford the title compound (3.05 g) as a yellow solid with a melting point of 56 to 57 ° C.

Elemental Analysis%: C ₁₇ H ₁₉ N ₃ O ₄ S

Found: C, 56.8; H, 5.3; N, 11.7;

Calculated: C, 56.5; H, 5.3; N, 11.6.

(D) 1- (4-aminophenylthio) -2- [N- (4-aminophenethyl) -N-methylamino] ethane

The title compound is prepared by hydrogenation of 2- [N-methyl-N- (4-nitrophenethyl) amino] -1- (4-nitrophenylthio) ethane on Raney nickel according to the method of Example 7 (B). . Nmr (CDCl ₃ ) ppm, δ = 7.25 (d, 2H); 6.98 (d, 2 H); 6.60 (m, 4 H); 2.92 (t, 2 H); 2.60 (m, 6 H); 2.32 (s, 3 H).

(E) 1- (4-methanesulfonamidophenylthio) -2- [N- (4-methanesulfonamidophenethyl) -N-methylamido] ethane

The title compound, having a melting point of 160 to 163 ° C., is prepared by mesylating the product of part (D) using methanesulfonic anhydride according to the method of Example 7 (C).

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₄ S ₃

Found: C, 49.5; H, 6.1; N, 8.6;

Calculated: C, 49.9; H, 5.95; N, 9.2.

Example 18

The following compounds are part of Example 17 above starting from the corresponding starting material except that the reducing step (D) is performed with SnCl ₂ in hydrochloric acid and the mesylation step (E) is with methanesulfonyl chloride in pyridine It is prepared similarly to the method of (A) to (E).

Starting material 2-chloro-4-nitrophenol is described in C.A., 34, 5574 (1940).

Example 19

(A) 1- (4-methanesulfonamidophenoxy) -2- [N-methyl-N- (4-nitrophenethyl) amino] ethane

N-methyl-4-nitropenethylamine (1.1 g), 2- (4-methanesulfonamidophenoxy) ethyl chloride (1.5 g), sodium bicarbonate (0.5 g) and sodium iodide in acetonitrile (100 ml) 0.9 g) The suspension is stirred at reflux for 4 days. After evaporation to dryness, the resulting oil is partitioned in 2N aqueous sodium bicarbonate solution and methylene chloride. After two additional extractions with methylene chloride, the organic layers are combined, washed with saturated brine solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting brown oil is eluted with ethyl acetate and chromatographed on silica (trade name “Kieselgel 60”) and the fractions collected and evaporated to give the title compound (0.9 g) as a yellow solid.

Nmr (CDCl ₃ ), δ = 2.45 (s, 3H); 2.86 (m, 6 H); 3.0 (s, 3 H); 4.2 (t, 3 H); 6.86 (d, 2 H); 7.22 (d, 2 H); 7.4 (d, 2 H); 8.15 (d, 2 H)

(B) 1- (4-methanesulfonamidophenoxy) -2- [N-methyl-N- (4-aminophenethyl) amino] ethane

A solution of 1- (4-methanesulfonamidophenoxy) -2- [N-methyl-N- (4-nitrophenethyl) amino] ethane (0.9 g) in ethanol (100 ml) was added to Raney Nickel (trade name, Nicat 102). Stir for 16 hours at room temperature under tritium pressure in the presence of "). The reaction mixture is filtered and evaporated to dryness. The resulting solid is crystallized from toluene to give the title compound (0.6 g) as a yellow crystal with a melting point of 155 to 157 ° C. do.

Elemental Analysis%: C ₁₈ H ₂₅ N ₃ O ₃ S

Found: C, 59.9; H, 7.1; N, 11.2;

Calculated: C, 59.5; H, 7.0; N, 11.6.

(C) 1- (4-methanesulfonamidophenoxy) -2- [N-4-methanesulfonamidophenethyl) -N-methylamino] ethane

Methanesulfonyl chloride (35.4 μl) in a solution of 1- (4-methanesulfonamidophenoxy) -2- [N-methyl-N- (4-aminophenethyl) amino] ethane (0.15 g) in anhydrous pyridine (3 ml) ) Is added dropwise and the mixture is stirred overnight at room temperature. After evaporation, the resulting oil is partitioned in 2N aqueous sodium bicarbonate solution and methylene chloride. After two additional extractions with methylene chloride, the organic layers are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting colorless solid (0.135 g) is crystallized from hexane / ethyl acetate to give the title compound (0.1 g) with a melting point of 151 to 152 ° C. This was spectroscopically confirmed to be the same as the product of Example 7 (C).

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₅ S ₂

Found: C, 51.6; H, 6.2; N, 9.2;

Calculated: C, 51.9; H, 6. 15; N, 9.4.

Example 20

(A) 1- (4-nitrophenoxy) -2- [N-methyl-N- (4-methanesulfonamidophenethyl) amino] ethane]

N-methyl-4-methanesulfonamidophenethylamine (1.0 g) in acetonitrile (100 ml) (see Preparation Example 8), 2- (4-nitrophenoxy) ethyl bromide (1.2 g) (see: CA, 54, 11046a), potassium carbonate (0.67 g) and sodium iodide (0.72 g) solutions are stirred at reflux for 3 days. After evaporation to dryness, the oil residue is partitioned in water and methylene chloride. After two additional extractions with ethylene chloride, the organic layers are combined, washed with saturated brine solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting yellow oil is dissolved in hot methanol and cooled to afford the crystallized title compound (1.2 g) as a colorless solid.

Nmr (CDCl ₃ ), δ = 2.48 (s, 3H); 2.82 (m, 4 H); 2.93 (t, 2 H); 3.02 (s, 3 H); 4.18 (t, 2 H); 6.98 (d, 2 H); 7.18 (d, 2 H); 7.22 (d, 2 H); 8.15 (d, 2 H).

(B) 1- (4-aminophenoxy) -2- [N-methyl-N- (4-methanesulfonamidophenethyl) amino] ethane, dihydrochloride

1- (4-nitrophenoxy) -2- [N-methyl-N- (4-methanesulfonamidophenethyl) amino] ethane in ethanol (50 ml) containing 5% Pd / C (0.1 g) 1.0 g) The solution is stirred at 1 hydrogen pressure (50 psi) for 4 hours. After the reaction mixture is filtered, the solvent is evaporated to give a brown oil. The oil is purified by column chromatography eluting with methylene chloride on silica (trade name "Kieselgel 60"). Appropriate fractions are combined and evaporated to yield a yellow oil (0.5 g). The oil is dissolved in ethyl acetate and an ethereal solution of hydrochloric acid is added until the precipitation is complete. The resulting colorless solid is washed with anhydrous ether to give the title compound (0.35 g) having a melting point of 220 to 223 ° C.

Elemental analysis%: C ₁₈ H ₂₅ N ₃ O ₅ S · 2HCl. 1 / 2H ₂ O

Found: C, 48.4; H, 6.4; N, 9.0;

Calculated: C, 48.5; H, 6.3; N, 9.4.

(C) 1- (4-methanesulfonamidophenoxy) -2- [N- (4-methanesulfonamidophenethyl) -N-methylamino] ethane

The title compound was prepared using 1- (4-aminophenoxy) -2- [N-methyl-N- (4-methanesulfonamidophenethyl) using mesyl chloride in pyridine according to the method of Example 19 (C). Prepared by mesylating amino] ethane dihydrochloride hemihydrate (95 mg). It was spectroscopically confirmed that the obtained compound (30 mg) was identical to the product of Example 7 (C).

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₅ S ₂

Found: C, 51.6; H, 6.3; N, 9.3;

Calculated: C, 51.9; H, 6. 15; N, 9.4.

Example 21

1- (4-methanesulfonamidophenoxy) -2- [N- (4-methanesulfonamidophenethyl) -N-methylamino] ethane

A solution of 4- [2- (methanesulfonyloxy) ethyl] methanesulfonanilide (0.3 g) and 4- [2- (methylamino) ethoxy] methanesulfonanilide (0.38 g) in ethanol (50 ml) was added for 6 hours. Reflux. After evaporation to dryness, the residue is partitioned in 2N aqueous sodium bicarbonate solution and methylene chloride. After two additional extractions with methylene chloride, the organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered and evaporated to dryness. The resulting brown oil is eluted with methylene chloride and chromatographed on silica (trade name "Kieselgel 60") to collect and evaporate the appropriate fractions. The resulting colorless solid is crystallized from ethyl acetate to give the title compound (0.21 g) having a melting point of 150 to 152 ° C. The same as the product of Example 7 (C) was confirmed spectroscopically.

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₅ S ₂

Found: C, 51.6; H, 6.3; N, 9.3;

Calculated: C, 51.9; H, 6. 15; N, 9.4.

Example 22

1- (4-methanesulfonamidophenoxy) -2- [N- (4-methanesulfonamidophenethyl) -N-methylamino] ethane

A mixture of 4- [2- (methylamino) ethyl] methanesulfonanilide (0.49 g), 4- (2-chloroethoxy) methanesulfonanilide (0.5 g) and sodium bicarbonate (0.17 g) in ethanol (50 ml) was refluxed. Stir for 3 days. After evaporation to dryness, the residue is partitioned in 2N aqueous sodium bicarbonate solution and methylene chloride. After two additional extractions with methylene chloride, the combined organic layers are washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting oil is eluted with methylene chloride and chromatographed on silica (trade name "Kieselgel 60") to collect and evaporate the appropriate fractions. The resulting solid is crystallized from ethyl acetate to give the title compound (0.25 g) having a melting point of 150 to 152 ° C. The same as the product of Example 7 (C) was confirmed spectroscopically.

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₅ S ₂

Found: C, 52.3; H, 6.3; N, 9.2;

Calculated: C, 51.9; H, 6. 15; N, 9.4.

Example 23

(A) N, N-bis- (4-nitrophenethyl) methylamine

The title compound is a known compound which is separated as a by-product (7%) in the reaction of 4-nitrostyrene and methylamine. See Journal Organic Chemistry 1956 Vol. 21p. 45.]. However, it is preferred to prepare the compounds by the route described below.

4-nitrophenethyl bromide (2.6 g, 11.3 mmol), N-methyl-4-nitropenethylamine (2.0 g, 11.3 mmol) and potassium carbonate (1.6 g, 11.3 mmol) in acetonitrile at reflux for 4 days Stir. The solvent is removed and the residue is dissolved in ethyl acetate, washed three times with aqueous sodium carbonate solution and three times with brine, then dried over MgSO ₄ and evaporated. The resulting oil is chromatographed on silica, eluting with methanol (0-2%) containing methylene chloride. Appropriate fractions were combined and evaporated to yield an orange oil which was triturated with hexane, filtered and dried to give the title compound (1.3 g) with a melting point of 70 to 71 ° C. as an orange powder.

Elemental Analysis%: C ₁₇ H ₁₉ N ₃ O ₄

Found: C, 61.7; H, 5.75; N, 12.5;

Calculated: C, 62.0; H, 5.8; N, 12.8.

Other methods of preparing N, N-bis- (4-nitrophenethyl) methylamine

4-nitrophenethyl bromide (1.0 g, 4.35 mmol) and 33% methylamine in water (10 ml) are stirred together at 55 ° C. for 2 hours. The reaction mixture is cooled and the resulting precipitate is collected by filtration, eluted with methanol (0-5%) containing methylene chloride and purified by column chromatography on silica. Appropriate fractions are combined and evaporated to yield the title compound (0.19 g) with a melting point of 73 to 75 ° C.

Elemental Analysis%: C ₁₇ H ₁₉ N ₃ O ₄

Found: C, 62.2; H, 5.9; N, 12.6;

Calculated: C, 62.0; H, 5.8; N, 12.8.

(B) N, N-bis (4-aminophenethyl) methylamine

A solution of N, N-bis- (4-nitrophenethyl) methylamine (1.2 g, 3.6 mmol) in ethanol (50 ml) containing 5% Pd / C (0.15 g) was used for 4 hours under 1 hydrogen pressure (50 p.si). Stir while. The reaction mixture is filtered and the solvent is evaporated to yield the title compound (1.0 g) as an oil which is used directly without further purification.

Nmr (CDCl ₃ ), δ = 6.7 (q, 8H); 3.4 (brs, 4H); 2.6 (s, 8 H); 2.3 (s, 3 H).

(C) N, N-bis- (4-methanesulfonamidophenethyl) methylamine

Methanesulfonic anhydride (1.29 g, 7.4 mmol) was added N, N-bis- (4-aminophenethyl) methylamine (1.0 g, 3.7 mmol) and triethylamine (1 ml, 7.4 mmol) in anhydrous methylene chloride (50 ml). It is added to the solution and stirred at room temperature for 2 hours. Methanesulfonic anhydride (1.29 g, 7.4 mmol) is added and the reaction mixture is stirred for a further 2 hours. The solvent is removed and the residue is dissolved in methylene chloride, washed three times with aqueous sodium bicarbonate solution and three times with brine, dried over MgSO ₄ and evaporated. The resulting oil is eluted with methanol (0-5%) containing methylene chloride and chromatographed on silica to combine the appropriate fractions and evaporate to give the title compound (0.29 g) with a melting point of 170 to 171 ° C.

Elemental Analysis%: C ₁₉ H ₂₇ N ₃ O ₄ S ₂

Found: C, 53.15; H, 6.5; N, 9.7;

Calculated: C, 53.6; H, 6.4; N, 9.8 ^* .

N.M.R. (TEAD), delta = 7.1 (q, 8H); 3.5 (m, 4 H); 3.3 (m, 4 H); 3.0 (s, 6H); 2.95 (s, 3 H).

* Samples containing trace amounts of methylene chloride (1/20 mol CH ₂ Cl ₂ as determined by ¹ Hn.mr spectroscopy)

Example 24

(A) N- (4-nitrophenethyl) -4-nitrophenethylamine

4-nitrophenethylamine (4 g), 4-nitrophenethyl bromide (5.54 g) and potassium carbonate (3.32 g) are heated under reflux in acetonitrile (50 ml) for 2 days. The solvent is evaporated and the residue is dissolved in ethyl acetate, then washed three times with aqueous sodium carbonate solution and three times with brine. The organic phase is dried over Na ₂ SO ₄ , filtered and evaporated, and the oil residue is purified by chromatography on silica, eluting with methanol (0-5%) containing methylene chloride. The product-containing fractions are combined and the solvent is evaporated and then recrystallized from ethyl acetate / hexanes to give the title compound (2.0 g) as a solid having a melting point of 86 to 91 ° C.

Elemental Analysis%: C ₁₈ H ₁₇ N ₃ O ₄

Found: C, 60.7; H, 5.6; N, 13.1;

Calculated: C, 60.9; H, 5.4; N, 13.3.

(B) N, N-bis- (4-nitrophenethyl) ethylamine

To the product of part (A) (0.75 g) and potassium carbonate (0.33 g) in acetonitrile (20 ml) is added dropwise ethyl iodide (0.37 g) and the reaction mixture is heated at reflux for 18 h. The reaction mixture is then evaporated to dryness and the residue is dissolved in methylene chloride, washed twice with aqueous sodium carbonate solution and twice with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The oil residue is eluted with methanol (0-2%) containing methylene chloride on silica and purified by column chromatography. The product containing fractions were combined and evaporated to dryness to afford the title compound (0.47 g) as an oil.

Elemental Analysis%: C ₁₈ H ₂₁ N ₃ O ₄

Found: C, 62.7; H, 6.0; N, 12.7;

Calculated: C, 63.0; H, 6.2; N, 12.2.

(C) N, N-bis (4-aminophenethyl) ethylamine

N, N-bis- (4-nitrophenethyl) ethylamine (0.45 g) was reduced using H ₂ / Pd / C in a similar manner to Example 23 (B) to give the title compound (0.32 g). .

Nmr (CDCl ₃ ) δ = 7.05 (d, 2H); 6.7 (d, 2 H); 3.55 (wide s, 4H); 2.70 (m, 10 H); 1.1 (t, 3 H).

(D) N, N-bis- (4-methanesulfonamidophenethyl) ethylamine

N, N-bis- (4-aminophenethyl) ethylamine (0.3 g) acylated with methanesulfonyl chloride in a similar manner to Example 19 (C) to form the title compound (0.12 g) with a melting point of less than 60 ° C. Prepared as (foam).

Elemental analysis%: C ₂₀ H ₂₉ N ₃ O ₄ S _{2 1/4} H ₂ O

Found: C, 54.1; H, 6.8; N, 9.2;

Calculated: C, 54.1; H, 6.7; N, 9.5.

In the following preparation examples all temperatures are in degrees Celsius, illustrating the preparation of certain new starting materials, some of which also form part of the present invention.

Preparation Example 1

3- (2-chloroethoxy) benzamide

To a solution of 3-hydroxy benzamide (21.6 g) in methyl ethyl ketone (“MEK”) is added 2-chloroethyl p-toluene sulfonate (55.46 g) and potassium carbonate (16.0 g). After stirring for 6 hours at reflux, the mixture obtained is poured into water and the colorless solid is filtered off. Crystallization from ethanol affords the title compound (22.2 g) with a melting point of 125 to 126 ° C.

Elemental Analysis%: C ₉ H ₁₀ ClNO ₂

Found: C, 53.7; H, 5.3; N, 6.9;

Calculated: C, 54.1; H, 5.05; N, 7.0.

Preparation Example 2

2- (2-chloroethoxy) -5-methylbenzamide

The title compound, having a melting point of 111-113 ° C., is prepared analogously to preparation example 1 from the corresponding starting material.

Elemental Analysis%: C ₁₀ H ₁₂ ClNO ₂

Found: C, 56.4; H, 5.65; N, 6.3;

Calculated: C, 56.2; H, 5.7; N, 6.6.

Preparation Example 3

4- {4- [2-chloroethoxy] benzoyl} morpholine

4- (2-chloroethoxy) benzoyl chloride (5.0 g) is dissolved in anhydrous methylene chloride and stirred with cooling to 0 ° C. Morpholine (4.0 g) is added dropwise and the mixture is stirred at room temperature for 2 days. The resulting colorless solid is filtered off and the solution is left to crystallize the title compound (5.5 g) having a melting point of 102 to 104 ° C.

Elemental Analysis%: C ₁₃ H ₁₆ CINO ₃

Found: C, 58.1; H, 6.0; N, 5.25;

Calculated: C, 57.9; H, 6.0; N, 5.2.

Preparation Example 4

N, N-diethyl-4- (2-chloroethoxy) benzamide

The title compound with a melting point of 80 to 81 ° C. is prepared analogously to the above preparation examples from the corresponding starting materials.

Elemental Analysis%: C ₁₂ H ₁₈ ClNO ₂

Found: C, 60.8; H, 7.0; N, 5.3;

Calculated: C, 61.05; H, 7.1; N, 5.5.

Preparation Example 5

5-methyl-2-nitrophenyl 2'-bromoethyl ether

5-Methyl-2-nitrophenol (5.0 g) and potassium carbonate (4.6 g) in butanone (100 ml) are stirred together at room temperature for 0.5 h. 1,2-dibromo ethane (3.1 g) is then added and the mixture is stirred at reflux for 2 days. After evaporation to dryness, distilled water is added and the mixture is extracted three times with methylene chloride. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated to remove the yellow solid obtained by filtration and the solution was evaporated to low volume for the title compound having a melting point of 48 to 49 ° C. used in Example 10. Is obtained as colorless crystals.

Nmr (CDCl ₃ ), ppm δ = 7.8 (d, 1H); 6.9 (m, 2 H); 4.42 (t, 2 H); 3.7 (t, 2 H); 2.45 (s, 3 H).

3-nitrophenyl 2'-bromoethyl ether and 2-nitrophenyl 2'-bromoethyl ether, respectively used as starting materials in Examples 8 and 9, are known compounds [J. Med. Chem., (1970), 13 (6), 1149 and C.A., 61, 601a].

Preparation Example 6

(A) 1- [N-methyl-N- (4-nitrophenethyl) amino] -2-hydroxypropane

A solution of N-methyl-4-nitrophenethylamine (1.8 g) and propylene oxide (0.66 g) in ethanol (50 ml) is stirred at reflux for 5 hours. After evaporation to dryness, the orange oil residue is eluted with ethyl acetate, chromatographed on silica (trade name "Kieselgel 60") and the appropriate fractions collected and evaporated to afford the title compound as a yellow oil.

Nmr (CDCl ₃ ) ppm, δ = 1.1 (d, 3H); 2.3 (m, 2 H); 2.32 (s, 3 H); 2.75 (m, 2 H); 2.9 (m, 2 H); 3.15 (Broad, 1H); 3.72 (m, 1 H); 7.15 (d, 2 H); 8.18 (d, 2 H).

(B) 1- [N-methyl-N- (4-nitrophenethyl) amino] -2-chloropropane

Thionyl chloride (50 ml) is added dropwise to 1- [N-methyl-N- (4-nitrophenethyl) amino] -2-hydroxypropane (1.5 g) with stirring and cooling in an ice / water bath. After stirring for 1 hour at room temperature, the solution is refluxed for an additional 2 hours on a medium bath. The solution is evaporated to dryness and the oil residue is partitioned between 2N aqueous sodium carbonate solution and ethyl acetate. After further extraction with ethyl acetate twice, the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting brown oil is chromatographed on silica eluting with ethyl acetate (trade name, "Kieselgel 60"), then the appropriate fractions are collected and evaporated to give the title compound (0.75 g) as a yellow oil.

Nmr (CDCl ₃ ), ppm δ = 1.48 (d, 3H); 2.35 (s, 3 H); 2.75 (m, 6 H); 4.02 (q, 1 H); 7.4 (d, 2 H); 8.18 (d, 2 H).

(C) 1- [N-methyl-N- (4-nitrophenethyl) amino] -2- (4-nitrophenoxy) -propane and 2- [N-methyl-N- (4-nitrophenethyl) Amino] -1- (4-nitrophenoxy) propane

4-nitrophenol (0.41 g) is added to a solution of sodium (0.075 g) in ethanol (50 ml) and the solution is stirred at room temperature for 1 hour. 1- [N-methyl-N- (4-nitrophenethyl) amino] -2-chloropropane (0.75 g) is added and the solution is stirred at reflux for 3 days. The solution is evaporated to dryness and the oil residue is partitioned between methylene chloride and water. After two additional extractions with methylene chloride, the combined organic layers are washed with saturated brine solution, dried over anhydrous magnesium sulfate, filtered and dried. The resulting orange oil (1.0 g) is chromatographed on silica (trade name, "Kieselgel 60"), eluting with 1: 1 hexanes: ethyl acetate.

The minimum polar product fractions are collected and evaporated to give the first-mentioned title compound (0.25 g) as a yellow oil.

Nmr (CDCl ₃ ) ppm: δ = 1.3 (d, 3H); 2.4 (s, 3 H); 2.75 (m, 6 H); 4.58 (q, 1 H); 6.91 (d, 2 H); 7.35 (d, 2 H); 8.1 (d, 2H); 8.2 (d, 2H).

The more polar product fractions were collected and evaporated to afford the second-mentioned title compound (0.3 g) as a yellow solid. This is n.m.r. Determine again spectroscopically.

Nmr (CDCl ₃ ) ppm: δ = 1.1 (d, 3H); 2.4 (s, 3 H); 2.85 (m, 4 H); 3.2 (q, 1 H); 3.95 (m, 2 H); 6.92 (d, 2 H); 7.35 (d, 2 H); 8.12 (d, 2 H); 8.2 (d, 2H).

Preparation Example 7

4- [2- (methanesulfonyloxy) ethyl] methanesulfonanilide

To a stirred solution of 4-aminophenethyl alcohol (41.15 g) in pyridine (350 ml) is added dropwise methanesulfonyl chloride (50 ml) at 0 ° C. over 0.5 h. The mixture is allowed to warm up to room temperature and stirred overnight. The mixture is poured into water (700 ml) to crystallize orange solid therefrom. After filtration, the solid is dissolved in methylene chloride, dried over magnesium sulfate, filtered and the filtrate is evaporated again. The resulting solid is crystallized from ethyl acetate to give the title compound (45.5 g) having a melting point of 136 to 137 ° C.

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

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

Calculated: C, 40.9; H, 5. 15; N, 4.8.

Preparation Example 8

4- [2- (methylamino) ethyl] methanesulfonanilide

To a solution of 4- [2- (methanesulfonyloxy) ethyl] methanesulfonanilide (10.3 g) in ethanol (20 ml) is added an aqueous methylamine solution (30 ml of 33% solution) in industrial methylated spirit. The mixture is heated in a pressure vessel with stirring at 85 ° C. for 17 hours. After cooling, the resulting solution is evaporated to dryness and the residue is dissolved in water and basified by addition of sodium hydroxide (1.4 g) in water (12 ml) to the resulting solution. Evaporation gives an off-white solid, which is eluted with methylene chloride / methanol (3: 1) on silica (trade name "Kieselgel 60") and chromatographed. Appropriate fractions are collected and evaporated to yield an off-white solid (4.8 g) and crystallized from ethyl acetate / methanol to give the title compound (1.8 g) with a melting point of 133 to 135 ° C.

Elemental Analysis%: C ₁₉ H ₁₆ N ₂ O ₂ S

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

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

Preparation Example 9

4- (2-chloroethoxy) methanesulfonanilide

To a solution of 4- (2-chloroethoxy) aniline hydrochloride (9.5 g) and methanesulfonic anhydride (12.0 g) in methylene chloride (100 ml) was added dropwise with cooling triethylamine (25 ml) and the mixture was allowed to stand at room temperature overnight. Stir. The resulting mixture is partitioned in 2N aqueous sodium bicarbonate solution and methylene chloride. After two additional extractions with methylene chloride, the organic layers are combined, dried over magnesium sulfate, filtered and evaporated to dryness. The resulting solid (9.5 g) is crystallized from methanol after impurity filtration to give the title compound (5.6 g) as a light pink crystal having a melting point of 111 to 114 ° C.

Nmr (CDCl ₃ ) ppm: δ = 2.84 (s, 3H); 3.8 (t, 2 H); 4.2 (t, 2 H); 6.75 (d, 2 H); 7.15 (d, 2 H); 9.0 (broad s, 1H).

Preparation Example 10

4- [2- (methylaminoethoxy)] methanesulfonanilide hydrochloride

A suspension of 4- (2-chloroethoxy) methanesulfonanilide (12.7 g) in methylamine solution (160 ml of 33% solution) in industrial methylated spirits is heated with stirring at 100 ° C. overnight in a pressurized vessel. The dark solution produced after cooling is evaporated to dryness. The residue is crystallized from ethanol to give the title compound (10.1 g) having a melting point of 192 to 194 ° C. as a colorless solid.

Elemental Analysis%: C ₁₀ H ₁₆ N ₂ O ₃ S. HCl

Found: C, 42.9; H, 6.0; N, 9.9;

Calculated: C, 42.8; H, 6.1; N, 10.0.

Preparation Example 11

Methyl 4- (2-chloroethoxy) benzoate

Methyl 4-hydroxy benzoate (15.2g, 0.1M), 2- (benzenesulfonyloxy) ethylchloride (28.65g, 0.12M) and potassium carbonate (19.15g) in 4-methylpentan-2-one (170ml) , 0.1M) The mixture is stirred at reflux for 24 h. After cooling, distilled water (170 ml) is added and the organic phase is separated off. The yellow solid obtained by evaporation to dryness is crystallized from ethanol to give the title compound (13.3 g) having a melting point of 56 to 58 ° C.

Nmr (CDCl ₃ ) δ = 8.02 (d, 2H); 6.96 (d, 2 H); 4.3 (t, 2 H); 3.92 (s, 3 H); 3.88 (t, 2 H).

Preparation Example 12

4- (2-chloroethoxy) benzamide

4-hydroxybenzamide (194 g, 1.25 M), 2- (benzenesulfonyloxy) ethyl chloride (359 g, 1.8 M) in butan-2-one (2.16 L), and potassium carbonate (172.8 g, 1.25 M) The mixture is stirred at reflux for 24 h. After cooling, distilled water (2.0 L) is added and the resulting precipitate is filtered off, washed with water and dried. Crystallization with ethanol gave the title compound (232.0 g) having a melting point of 66 캜.

Elemental Analysis%: C ₁₀ H ₁₁ N ₂ ClO ₃

Found: C, 54.2; H, 5.0; N, 6.9;

Calculated: C, 54.25; H, 5.1; N, 7.0.

Preparation Example 13

2- (4-nitrophenoxy) ethyl chloride

4-nitrophenol (139 g, 1 mole), 2- (benzenesulfonyloxy) ethyl chloride (220.5 g, 1 mole-see in Ber. (1920), 53, 1836 in methyl ethyl ketone ("MEK"-1000 ml)) ) And anhydrous potassium carbonate (138 g, 1 mole) mixture is stirred at reflux for 16 h. After cooling, the mixture is poured into water and the organic layer is separated. After two additional extractions with methyl ethyl ketone, the combined organic fractions are dried over MgSO ₄ , filtered and evaporated. The resulting solid is crystallized from ethanol to give the title compound (165.8 g) with a melting point of 60 ° C.

Elemental Analysis%: C ₈ H ₈ ClNO ₃

Found: C, 47.65; H, 4.0; N, 7.0;

Calculated: C, 47.7; H, 4.0; N, 7.0.

Claims (17)

A compound of formula (A) or a salt thereof.

Wherein R ^a is —NO ₂ , —NH ₂ or —NHSO ₂ R ¹ , wherein R ¹ is a C ₁ -C ₄ alkyl group, and R ^b is —NO ₂ , —NH ₂ or R ³ [ Wherein R ³ is —NHSO ₂ (C ₁ -C ₄ alkyl) or —CONR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each independently H or C ₁ -C ₄ alkyl or a nitrogen attached thereto Together with the atom represents a 1-pyrrolidinyl, piperidino, morpholino or N-methylpiperazin-1-yl group), provided that if one of R ^a and R ^b is -NO ₂ , The remainder are not —NH ₂ , X is oxygen, S or a direct bond, Y is an ethylene group unsubstituted or substituted by a methyl group, and “alk” is ethylene, trimethylene, unsubstituted or substituted by a methyl group Or a tetramethylene group, R is C ₁ -C ₄ alkyl and R ² is H, halo, CF ₃ or C ₁ -C ₄ alkyl. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

Wherein R and R ¹ are each independently C ₁ -C ₄ alkyl, X is oxygen, S or a direct bond, Y is an ethylene group unsubstituted or substituted by a methyl group, and “alk” is unsubstituted Or ethylene, trimethylene and tetramethylene groups, substituted by methyl groups, R ² is H, halo, CF ₃ or C ₁ -C ₄ alkyl, and R ³ is of the formula —NHSO ₂ (C ₁ -C ₄ alkyl) ) Or -CONR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently H or C ₁ -C ₄ alkyl or together with the nitrogen atom attached to them 1-pyrrolidinyl, piperidino, morpholino Or an N-methylpiperazin-1-yl group). The compound of claim 2, wherein R ¹ is methyl. The compound of claim 2 or 3, wherein R is methyl or ethyl. The compound of claim 4, wherein R is methyl. The compound of claim 2 or 3, wherein X is oxygen. The compound of claim 2 or 3, wherein Y is — (CH ₂ ) ₂ —. The compound of claim 2 or 3, wherein R ² is H, Cl or CH ₃ . The compound of claim 8, wherein R ² is H. 10. The compound according to claim 2 or 3, wherein R ³ is -NHSO ₂ CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON (C ₂ H ₅ ) ₂ or -CO

Phosphorus compounds. The compound of claim 10, wherein R ³ is —NHSO ₂ CH ₃ . The compound of claim 2 having the structure

The compound of claim 2 having the structure

The compound of claim 2, wherein Y is — (CH ₂ ) ₂ — and X is oxygen or S. 4. The compound of claim 2, wherein Y is — (CH ₂ ) ₂ — and X is a direct bond. A pharmaceutical composition useful as a therapeutic agent for arrhythmia, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier as claimed in claim 2. The compound of claim 1, wherein R ^a , R ^b , R, R ² , X, Y and alk are as defined in claim 1, wherein at least one of R ^a and R ^b is nitro or R ^a and R ^b A compound of formula (A), wherein at least one of is amino.