CS271489B2 - Method of alkylsulphonamidophenethylamines' sulphonamidoderivatives production - Google Patents

Abstract

The method of production of sulfonamide derivates of alkyl sulfonamide phenethylamines is of a general formula I, where alk is C1-4-alkyl, R<1> is C1-4-alkyl and Het is the rest of the formula E, F or G, in which R<2> is hydrogen, methyl or ethyl, X is oxygen, sulphur or the rest of NR<4>, where R<4> is hydrogen or methyl and their pharmaceutically utilizable salts, characteristic by the fact that a compound of the general formula B, where R<a> is an amino group or the rest NHSO2alk and Het is the rest of the formula E, F or G; which can instead of -NHSO2alk configuration contain also an amino group providing that in the starting substance molecule there is at least one amino group is let to react with the C1-4-alkansulfonylchloride or -bromide or with an anhydride of C1-4-alkan-sulphonic acid. Finally the product of the general formula I is converted to salt. The produced compounds are efficient as anti-arrhythmic active substances and can be used in pharmaceuticals.<IMAGE>

Description

The invention also relates to certain euphonamides which are effective as antiarrhythmic agents and to intermediates required for their manufacture.

The antiarrhythmic agents of the invention extend the duration of action potential in the cardiac evaluation of conductive tissue, thereby increasing refractory to premature stimuli. Thus, these agents are class III antiarrhythmic agents according to the Vaughan William Classification (Anti-Arrhythmic Actlon, 6M, Vaughan Williams, Academic Preee, 1980). These agents act in the atria, ventricles and conductive tissue both in vitro and in vivo and are therefore useful for the prevention and treatment of a wide variety of ventricular and eupraventricular arrhythmias, including atrial and ventricular fibrillation. Since the disclosed compounds do not change the rate at which impulses are conducted, they tend to have less tendency than current drugs (belonging mostly to Class I) to induce or worsen arrhythmias, and also produce less neurological side effects. Some of these compounds also exhibit some positive inotropic activity and are therefore particularly suitable for patients with impaired heart pumping function.

Accordingly, the invention provides compounds of Formula A

(AND)

in which

R is n-nitro, amino or -NHSO ₂ alk, where alk is C 1 -C 4 alkyl,

R ¹ represents an alkyl group of 1 to 4 carbon atoms and

Het represents the remainder of the formula

in which

R represents a hydrogen atom, a methyl or ethyl group,

R is nitro, amino or -NHSO ₂ alk, where alk is as defined above, and

CS 271 489 B2

X represents an oxygen atom, a sulfur atom or a NR ⁴ radical where R ⁴ represents a hydrogen atom or a methyl group, with the proviso that if one of R and R is nitro, the other of these is unsubstituted aainoacaoine, and salts thereof.

Compounds of formula A wherein R and R are -NHSOgalk are effective as antiarrhythmic agents. The remainder of the above are intermediates for synthesis.

Accordingly, the present invention also provides anti-arrhythmic agents of formula I

(I) in which

represents the residue-‰ <SC ₂ alk, ^k de alk represents an alkyl group of β 1 to 4 carbon atoms, represents an alkyl group of 1 to 4 carbon atoms, and

Het represents the remainder of the formula

in which

R represents a hydrogen atom, a netnyl group or an ethyl group,

R represents the radical -N1-SO4alk, where alk has the meaning given above and a

4

X represents an oxygen atom, a sulfur atom or a NR residue, wherein R represents a hydrogen atom or a methyl group, and pharmaceutically acceptable salts thereof.

In the compounds of formula (I), R is preferably -NHSO ₂ CH ₃ , R ¹ is preferably methyl or ethyl, R ² is preferably hydrogen or

Preferably, R ³ is -NHSO ₂ CH ₃ and X is preferably oxygen or sulfur.

The substituent R ³ preferably occupies position 6 or 7 when Het contains a quinolyl group, and position 5 or 6 in other cases (i.e., when the benzene ring is fused to a five membered heterocycle) ·

Preferred individual compounds are those of formulas IA and IB

(IA)

(IB)

Pharmaceutically useful eolls of the compounds of formula I include acid addition salts containing pharmaceutically acceptable anions such as hydrochlorides, hydroiodides, sulfates or hydrogen sulfates, phosphates or hydrogen phosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, benzoates, methanesulfonates , bsylates and p-toluene sulfonates. The salts described are prepared by conventional methods.

To determine the effect of the compounds of the invention on atrial refractory, true guinea pig hemi-sodium is placed in a bath containing physiological saline and one end thereof is connected to a force transducer. Tissue is stimulated at 1 Hz using surface electrodes. Effective refractory period (ERP) and e is measured so that, after every eighth basic stimulus (sp introduce premature impulse _(S2). The interval between and S ₂ are successively zvyěuje to stimulus S ₂ reproducibly induces advertised responses, which is defined as the ERP. Then, ae the concentration of the test compound required to increase the ERP by 25% (ED ₂₅ ) · ERP is also measured using the right guinea pig papillary muscle in physiological saline, stimulating the muscles at one end with bipolar electrodes and unipolar at the other end The electroprogram is recorded by electroprogram in the same way as above, the conductivity is determined from a digital oecilloscope with a memory by measuring the interval between the artificial stimulus and the electrogram peak (ie the time required for the pulse to travel through the entire length of the muscle).

Atrial and ventricular ERP are also measured on an anesthetized or weaned dog using extra stimuli. The atrium or right ventricle is kept at a constant frequency.

The compounds of formula I may be administered as such, but are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. The disclosed compounds can be administered to both patients suffering from arrhythmia as well as prophylactically to potential patients who are expected to develop arrhythmias. For example, the compounds may be administered orally in the form of tablets containing starch or lactose as carriers, or in the form of capsules containing either alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing coloring or flavoring agents. The compounds of the invention may also be administered by parenteral injection, for example intravenously, intramuscularly or subcutaneously. for parenteral administration, these substances are best used in the form of a sterile aqueous solution which may contain other soluble substances, such as salts or glucose, to render the solution isotonic.

For human medical applications for curative or prophylactic treatment of cardiac diseases such as ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation, oral doses of compounds of Formula I range from 2 to 160 mg per day for an average adult patient (70 kg) . This total dose can be administered in up to four divided doses per day. For intravenous administration, the dosage ranges from 1.0 to 20 mg per unit dose. In severe cardiac arrhythmias, the active compounds are administered intravenously to patients, and preferably administered intravenously to achieve a rapid transition to normal rhythm. Individual tablets or capsules for typical adult patients may therefore contain 2 to 50 mg of the active compound in a suitable pharmaceutically acceptable diluent or carrier. Oak It is known in the art that there may be various variations depending on the weight and condition of the patient being treated ·

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

The invention further provides a method of preventing or treating cardiac arrhythmias in human medicine, comprising administering to a patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above.

The invention also relates to the use of the compounds of the formula I or their pharmaceutically acceptable salts as medicaments, in particular as antiarrhythmic agents.

In a further aspect, the invention provides the use of compounds of Formula X or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the prevention or treatment of cardiac arrhythmias.

It is an object of the present invention to provide a compound of formula (X) and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (8):

in which

R ⁰ represents an amino group or an -NHSOgalk radical wherein alk is an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, and

Hst represents the remainder of the formula

CS 271 489 B2

or

in which

R and X are as defined above and

R ^b is an amino or -NHSO ₂ alk group, wherein alk is as defined above, without limiting the fact that R and R are not present -NHSO ₂ alk groups, reacts with alkanesulfonyl chloride or a C 1 -C 4 -bromide or anhydride alkanesulfonic acids having 1 to 4 carbon atoms, whereupon the resulting compound of formula I is optionally converted into its pharmaceutically acceptable salt. Of course, when both R ^d and R ^b are amino, at least two equivalents of the acylating agent are needed, and both -NHSO ₂ alk residues in the final product are naturally identical.

The reaction is typically carried out at room temperature and optionally in the presence of an acid acceptor, such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid acceptor is particularly needed when alkanesulfonyl chloride or bromide is used as acylating agent. This reaction is particularly preferably carried out using alkanesulfonyl chloride in pyridine. The product of formula (I) can then be isolated and purified in a conventional manner.

The starting materials for this annealing reaction can be prepared in a conventional manner, for example as follows t (a)

^K 2 ^CO 3> ^var P ^from reflux condenser, organic solvent

catalytic residrogenation (e.g. H ₂ / feyeyey-nickel, 344 kPa)

CS 271 4B9 B2

In the formulas shown in this scheme, R 1 and Het are as in Formula I and Q is a leaving group such as chlorine, bromine, iodine or methanesulfonyloxy · (b)

^K 2 ^CO 3 ^var P ^{0 <iz} P., ^et «ý® condenser, an organic solvent

catalytic hydrogenation (e.g. H 2 / Raney-nickel, 344 kPa)

In the formulas shown in this scheme, r 1 Het and Q have the meanings given above in scheme (a).

(c) Processes (a) and (b) described above can also be carried out using starting materials in which the substituent R1 in Het is not a C1 -C4 alkanesulfonamido group but a nitro group. In this case tsdy dinitroderlvát obtained intermediate, which may then be reduced by catalytic hydrogenation to the corresponding diamino derivative, ie · on the starting material of formula B in which both R ^a and R ⁸ are amino · (d)

alkSO ₉ NH - (CH ₂ ) ₂ KHB ¹ + Q-CH ₂ -Het ^ά \ (B ^b in Het = KO ₂ )

reflux, organic solvent

CS 271 489 B2

r ~ R ¹ alkSOzNH— ( —X | 2-- (CH ₂ ) ₂ -N-CH ₂ -Het (R ^b = NO ₂ ) IN = / catalytic hydrogenation (e.g. clad H ₂ / Raney-nickel, 344 kPa) i alkSO ₂ NH-- f R ¹ \ 1 2-- (CH ₂ ) ₂ -N-CH ₂ -Het (R ^b = NH ₂ )

In the formulas shown in this reaction scheme, alk and R 1 are C 1 -C 4 alkyl, Het in the first step is the nitrosubstituted heterocycle defined in formula (A) and Q is a leaving group as defined in process (a) above.

The starting materials used in processes (a) to (d) are either known or can be prepared by conventional techniques, for example as described in the preparations below.

The following examples illustrate the preparation of the compounds of formula (I).

Example 1

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

CH 2 SO 4 Cl, pyridine

CS 271 489 B2

To a solution of 0.78 g (1.68 mmol) of N-methyl-N- (3-methyl-5-aminobenzofur-2-yl-ethyl) -4-methanesulfonamidophenethylamine (see preparation 10V) in 7 ml of pyridine and dropwise 0.21 g (1.85 mmol) of methanesulfonyl chloride and the resulting solution was stirred at room temperature for 60 hours. The solvent was evaporated, the residue was triturated with toluene, the toluene was decanted, the residue was stirred with aqueous sodium bicarbonate, the precipitate was filtered off and recrystallized from methanol. Yield: 0.38 g. E. The title compound melts at 142-143.5 ° C.

N, 9.0; N, 9.0; Found _: C, 54.4; H, 5.8; N.

Example 2

N-Methyl-N- (5-methanesulfonamido-benzofuran-2-ylmethyl) -4-methanesulfonamino-phenethylamine

CH ₃ SO ₂ Cl, pyridine

CS 271 489 82

To a solution of 0.9 g (3.0 mmol) of N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (see Preparation 3) in 25 ml of pyridine was added dropwise 0.76 9 (6.6 mmol) of methanesulfonal chloride and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated, the residue was diluted with aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined organic extracts were dried over magnesium sulfate, evaporated and the residue purified by silica gel chromatography using ethyl acetate as eluent. The fractions containing the product were combined, evaporated and the solid residue was recrystallized from a mixture of ethyl acetate and methanol. Yield 0.35 g, m.p. 177-179 ° C.

Analysis calculated for: ^{C N HH} 25 NN SO ° ^S SS: C, 53.2; H, 5.6; N, 9.3; Found: C 53.2%, H 5.7%, N 9.0%

Example 3

N-Methyl-N- (5-methanesulfonamidobenzoxazol-2-methyl) -4-methanesulfonamidophenethylamine

CH ₃ SO ₂ N

0.45 g (1.5 mmol) of N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (see Preparation 1C) vs 20 ml of pyridine was treated with 0 ml under analogous conditions to Example 2. , 38 g (3.3 mmol) of methane sulfonyl chloride. Crystallization from ethanol gave 0.25 g of the title compound, m.p. 174-176 ° C.

Analysis: for ^C i9 ₂ ^H 4 ^N 4 ° 5 ^S 2 Calculated% C, 50.4 _t 5.35% H, 12.4% N;

Found: C, 50.4; H, 5.1; N, 12.4.

Example 4

N-Methyl-N- (6-methanesulfonamidobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

CS 271 489 B2

0.24 g (0.02 mmol) of N-methyl-N- (6-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (see Preparation 2) in 3 ml of pyridine ee was reacted in analogy to Example 2 , 21 g (1.6 mmol) of methanesulfonyl chloride. In a yield of 0.18 g ee, the title compound is obtained as an oil.

Analysis for ^ 20 ^ 25 ^ ⁸ 3θ5 2 requires 53.2% C, 8.6% H, 9.3% N;

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

Example 5

N-Methyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine

CS 271 489 B2

0.17 g (0.37 mmol) of N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethylamine (see Preparation 4) in 20 ml of pyridine ee was reacted under conditions analogous to Example 2 to 30 ° C. , 15 g (1.3 mmol) of methanesulfonyl chloride. After crystallization from ethyl acetate ее in a yield of 0.70 g, the title compound is obtained, m.p. 163-165 ° C.

Analysis calculated for ^C 21 ^H 26 ^N 4 ° 4 ^S 54.5% C, 5.7% H, 12.1% N | found: 54.3% C, 5.7% H, 12.1% N.

Example 6

N-Methyl-N- (5-methanesulfonamido-2-benzo (b) thymylmethyl) -4-methanesulfonamide

0.26 g of N-methyl-N- (5-amino-2-benzo [b] thienylmethyl) -4-aminophenethylamine (see Preparation 12) 9Θ reacted in pyridine with β 0.23 g of methanesulfonyl chloride · Obtained 0.167 g of the title compound, m.p. 175-177 ° C.

For ^C 20 ^H 25 ^N 3 ^O 4 ^S 3 calculated C 5.37%, H 5.39%, N 8.99%;

found 50.99% C, 5.39% H, 8.93 N.

Example 7

N-Methyl-N- (6-methanesulfonamidoquinolin-2-ylmethyl) -4-methanesulfonamidophenethylamine hydrochloride

CH ₃ SO ₂ Cl

HCl / ethyl ether

CS 271 489 82

hci.h ₂ o

0 * 51 g (1 * 23 mmol) of N-ethyl-N- (6-aminoquinol-2-ylaethyl) -4-methanesulfonamidoethylamine (see Preparation 118) was reacted in pyridine in a manner analogous to Example 2 to 0 * 1. g (1 * 29 mmol) of non-sulfanesulfonyl chloride. The free base of the title compound is obtained in the form of a resin. This resin was dissolved in ethyl acetate. The solution was diluted with ethereal hydrogen chloride and evaporated to dryness. The residue was triturated with ether (0 * 06 g) to afford the title compound * as a foamy solid, m.p. 96 ° C.

For ^C 22 ^H 28 ^N 4 ° 4 ^S 2 * ^HCl * ^H 2 ° calculated 49 * 75% C, 5 * 9% H. 10 * 5% N;

found 50 * 2% C * 5 * 5% H * 10 * 0% N.

Preparation 1 (A) 2-Chloromethyl-5-nitrobenzoxazole

HN.HC1

Cl

OH

Cl g (65 mmol) of 2-amino-4-nitrophenol and 15 * 4 g (97 * 5 mmol) of chloroacetimidate hydrochloride were refluxed in 100 ml of ethanol for 18 hours. The solvent was evaporated in vacuo and the residue was recrystallized from ethanol * to give the title compound, melting at 216-217 ° C, in a yield of 9.0 g.

Analysis calculated for: 45.2% C, 2.4% H * 13.2% N, found 45 * 15% C, 2.3% H, 13.25% N.

(B) N-Methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine

CS 271 409 03

A mixture of 2.05 g (13.4 mmol) of 2-chloromethyl-5-nitrobenzoxazole, 2.2 g (12.2 mmol) of N-methyl-4-nitrophenethylamine / □ · O. C ·, (1956), 21, 45), 1.05 g (13.4 mmol) of potassium carbonate and 2.0 g (13.4 mmol) of sodium iodide are heated to reflux in 50 ml of acetonitrile for 3 days. · The solvent is evaporated off, the residue is diluted with water. Extract three times with methylene chloride. Wash the combined organic extracts with water, dry over magnesium sulfate, filter and evaporate to dryness. The oily residue is diluted with ether, the supernatant is decanted off and evaporated to dryness. An orange-colored solid residue is obtained which, after recrystallization from isopropanol, yields the title compound. The yield of the product is 0.00 g.

@ 1 H-NMR (CDCl3): 8.6 (d, 1 H), 0.3 (dd, 1 H), 8.1 (d, 2 H), 7.6 (d, 1 H), 7, 35 (d, 2H), 3.95 (s, 2H), 2.95 (q, 2H), 2.85 (q, 2H), 2.5 (α, 3H).

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

H ₂ is P. eney-nickel

O

CS 271 489 B2

0.78 g (2.2 mmol) of N-methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine in 60 ml of methanol in the presence of 0.1 g of Reney-nickel was stirred in a hydrogen atmosphere for 18 hours under stirring. pressure 344.7 kPa. After this time, thin layer chromatography of the reaction mixture indicated consumption of most of the starting material. Chromatography is performed on silica gel plates using a 19: 1 mixture of methylene chloride and methanol as a solvent system. The reaction mixture is filtered, the filtrate is evaporated, the oily residue is azeotroped with toluene and then triturated with ether. The decanted ether layer, after evaporation, gave 0.46 g of the title compound as an oil which was used directly without further purification.

1 H-NMR (CDCl 3): 7.25 (d, 1H), 6.95 (dd, 3H), 6.65 (dd, 1H),

6.6 (d, 2H), 3.85 (8. 2H), 2.7 (e, 4H), 2.4 (e, 3H).

Preparations 2 to 4

The products of Preparations 2 to 3 are prepared in an analogous manner to Preparation 1C by reducing the corresponding dinitro compounds (see Preparations 6 and 5) using hydrogen and Raney nickel, which is operated in ethanol at 50 psi at room temperature for a period of time. 4 resp. 17 hours. The product of Preparation 4 was prepared in an analogous manner to Preparation 1C, but the reduction was carried out with hydrogen in the presence of palladium on carbon, in ethanol at a pressure of 207 kPa and lasted for 3 hours. The required starting dinitro compound is prepared as described in Preparation 8.

The above procedures can be illustrated by the following reaction scheme and the products produced are summarized below.

NO.

CS 271 489 B2

Ρ φ ж

AND

ю φ> со J-ч о.

Ή

о.

2Ž

CS 271 4-9 82

Preparation 5 (A) 4- (Isopropylidonaminoxy) n-trbenzene

To a suspension of 10.8 g (0.45 mol) of sodium hydride in 50 ml of dry tetrahydrofuran is slowly added a solution of 30 g (0.4 mol) of propanonoxime in 300 ml of dry tetrahydrofuran. After gas evolution had ceased, 100 ml of dimethylsulfoxide and 57.85 g (0.41 mol) of 4-fluoronitrobenzene were added. The reaction mixture was stirred at room temperature for 2 hours, then poured into water and extracted three times with ether. The combined ether extracts were washed with water and dried over magnesium sulfate to give the title compound, which was granulated in hexane and then filtered off. The product yield is 67 g. A sample of 7 g, after recrystallization from ethanol, yields 5 g of a substance, m.p. 104-106 ° C.

For ^C 8 ^{H 10 N} 2 ^O 3 calculated C 55.7%, H 5.2%, 14.4 &N; Found: C, 55.6; H, 5.05; N, 14.35.

(6) 2-Methyl-5-nitrobenzofuran

530 g of glacial acetic acid containing 25 g of hydrogen chloride gas are added in 60 g (0.309 mol) of 4- (1-isopropylidonaminoxy) nitrobenzene. The reaction mixture was heated at 100 ° C for 18 hours, then the solvent was evaporated and the residue was azeotroped with cyclohexane. The oily material obtained was diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with 10% aqueous sodium hydroxide solution and water and dried over magnesium sulfate and evaporated. Yield: 46 g. A sample of this product, weighing 5 g, gave after isolation from iso17

CS 271 489 B2 propanol 2.5 g of a substance with a melting point of 93 to 95 ° C ·

Analysis: for C _Q H ₇ NO ₃ Calculated 61.0% C 4.0% H 7.9% N;

found 61.2% C, 4.1% H, 7.9X N.

(C) 2-Bromomethyl-5-nitrobenzofuran

To a solution of 1.0 g (5.6 mmol) of 2-methyl-5-nitrobenzofuran and 50 mg of benzoyl peroxide in ml of carbon tetrachloride was added 1.1 g (6.2 µmol) of N-bromosuccinimide in portions and the mixture was irradiated with bright light The reaction mixture was cooled, filtered and evaporated to dryness. The residue was recrystallized from petroleum ether to give 0.75 g of the title compound, m.p. 96-98 ° C.

Analysis: for C _g HgBrNO ₃ Calculated 42.2% C 2.4% H 5.5% N;

Found: 41.7% C, 2.4% H, 5.3% N · (O) N-Methyl-N- (5-nitrobenzofur-2-ylmethyl) -4-nitrophenethylamine

CH ₂ Br ik ₂ co ₃ ; Nal

CS 271 489 B2

A mixture of 0.41 g (2.3 mmol) of N-methyl-4-nitrophenethylamine, 0.66 g (2.6 mmol) of 2-bromomethyl-5-nitrobenzofuran, 0.39 g (2.6 mmol) of sodium iodide and 0.36 g (2.6 mmol) of potassium carbonate is heated to reflux in 50 ml of acetonitrile for 8 days. The solvent was evaporated, water was added to the residue, and the mixture was extracted three times with methylene chloride. The combined organic extracts were washed with water, dried over magnesium sulphate and evaporated to a semi-solid residue which, after recrystallization from isopropanol, gave the title compound. Yield: 380 mg.

@ ³ H-NMR (dimethylsulfoxide / trifluoroacetic acid, ppm) .delta. 8.75 (s, 1H), 8.3 (d, 1H), 8.2 (d, 2H), 7.9 (d, 1H), 7.6 (d, 2H), 7.45 (s, 1H), 4.75 (t, 2H), 3.2 (t, 2H), 2.9 (s, 2H), 2.5 (β) , 3H).

Preparation 6 (A) 2-Bromomethyl-6-nitrobenzofuran

To a solution of 1.00 g (5.65 mmol) of 2-methyl-6-nitrobenzofuran and 20 mg of azobisisobutyronitrile in carbon tetrachloride was added 1.11 g (6.2 mmol) of N-bromosuccinimide (* N8S) and the mixture was irradiated heat to reflux for 1.5 hours with bright light. The solvent is evaporated, the residue is dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue was purified by silica gel column chromatography using a 7: 3 mixture of methylene chloride and hexane as eluent. Product containing fractions were combined and evaporated to give 1.43 g of the title compound. The analysis of the spectrum clearly shows that the product contains 20% 2-dibromoethyl 6-nitrobenzofuran, which is not necessarily removed and the product is therefore used directly without further purification.

CS 271 489 B2 (Θ) N-Methyl-N- (6-nitrobenzoxazol-2-ylmethyl) -4-nitrophthylamine

A mixture of 0.84 g (4.7 mmol) of N-methyl-4-nitrophenethylamine, 1.2 g (4.7 mmol) of 2-orommathyl-6-nitrobenzofuran, 0.7 g (4.7 mmol) of sodium iodide and 0.71 g (5.2 mmol) of potassium carbonate in acetonitrile was refluxed for 18 hours. The reaction mixture was cooled, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on eilica gel using a mixture of equal parts first. methylene chloride and hexane and then methylene chloride / methanol (19: 1) as eluents. The product containing fractions are combined, evaporated and the residue treated with activated carbon in ethanol. An oily product is obtained which solidifies on standing and recrystallized from ethanol. and methylene chloride gave 0.27 g of the title compound, m.p. 69-69.5 ° C.

Analysis: Calculated: C, 60.8; H, 4.8; N, 11.8.

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

¹ H NMR (CDCl 3): 8.3 (β, 1H), 8.15 (dd, 10), 8.1 (d, 2H),

7.55 (d, 1H), 7.35 (d, 2H), 6.65 (s, 1H), 3.8 (s, 2H), 2.95 (t, 3H), 2.75 (t , 3H),

2.4 (s, 3H).

Preparation 7 (A) 2-Hydroxymethyl-3-methyl-5-nitrobansofuran

CS 271 489 82

To a suspension of 1.1 g (15 mmol) of 3-methyl-5-nitrobenzofuran-2-carboxylic acid in tetrahydrofuran at 0 ° C was added dropwise 18.0 ml (18.0 mmol) of a 1M solution of diborane in tetrahydrofuran. The reaction mixture was stirred at 0 ° C for 30 minutes, then at room temperature for 18 hours, another portion of diborane solution (5.0 mL) was added, and the reaction mixture was sonicated for 2.5 hours. the solvent is evaporated, the residue is taken up in ethyl acetate, the solution is washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is purified by silica gel column chromatography using methylene chloride as eluent. Product containing fractions were combined and evaporated to give 0.96 g of the title compound. A sample of the product melts after recrystallization from ethyl acetate at 149-150 ° C.

Analysis: for C | q _q N0 ₄ Calculated 58.0% C 4.4% H 6.8% N;

found: 57.9% C, 4.2% H ₍ 6.7% N.

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

To a solution of 0.86 g (4.15 mmol) of 2-hydroxymethyl-3-methyl-5-nitrobenzofuran in 10 ml of methylene chloride containing 2 drops of pyridine was added dropwise 1.48 g (12.4 mmol) of thionyl chloride and the mixture was stirred for 24 hours at room temperature · The reaction mixture is diluted with water, the organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic layers were washed with aqueous sodium bicarbonate, dried over sodium sulfate and the solvent was evaporated. It yields 0.93 g of the title compound. part of this product melts after recrystallization from ethanol at 141-142 ° C.

Analysis: calculated for C 53ΟΗΗΗΟΝΟΝΟ: 53.2% C, 3.6% H, 6.2% N; .

Found: C, 52.95; H, 3.7; N, 6.0%.

Preparation 8

N-Methyl-N- (6-nitroquinol-2-ylmethyl) -4-nitrophenethylamino

CS 271 489 82

0.39 g (2.15 mmol) of N-methyl-4-nitro-phenethylamine and 0.40 g (2.1 mmol) of 2-chloromethyl-6-nitroquinoline and in 30 ml of ethanol were refluxed for 6 hours. The solvent was evaporated, the residue was diluted with 2M hydrochloric acid and extracted with methylene chloride. The aqueous layer was basified with aqueous sodium carbonate solution to about pH 12 and extracted three times with methylene chloride. The combined organic extracts were dried over magnesium sulfate and evaporated to an oily residue. The residue was purified by silica gel column chromatography using methylene chloride containing increasing amounts of methanol (from 0% to 1%) as eluent. Fractions containing product were combined and evaporated to a solid residue which, recrystallized from ethanol, gave 0.21 g of compound. mp 104-105 ° C.

Analysis: ^{C H} ig ig 4 ^N ° 4 Calculated 62.3% C, 4.95% H, 15.3% N;

Found S 2.4% C, 4.7% H, 15.2% N.

1 H-NMR (CDCl 3) δ 8.9 (d, 1H), 8.5 (dd, 1H), 8.3-8.1 (m, 3H),

7.6 (d, 1H), 7.35 (d, 1H), 3.95 (α, 2H), 3.0 (t, 2H), 2.8 (t, 2H), 2.4 (α) , 3H).

Preparation 9 (A) 4-Methanesulfonamidophenethyl methyl ester

CrUSOgCl pyridine

To a solution of 82.3 g (0.6 mol) of 4-aminophenethyl alcohol in 700 ml of pyridine is added dropwise

146.6 g (1.28 mol) of methanesulfonyl chloride were added and the mixture was stirred at room temperature for 18 hours. The reaction mixture is poured into 700 ml of water, the precipitate formed is filtered off, washed with water and dried and recrystallized from ethyl acetate. In a yield of 31 g, the title compound is obtained, m.p. 134-136 ° C. An additional 14.5 g of product is obtained by concentrating the mother liquors under vacuum.

CS 271 489 82 (В) N-Benzyl-N-ethyl-4-methanesulfonamidophenethylamine

g (34 mmol) of 4-methanesulfonamidophenethyl-butylate and 10 µl (67 mmol) of N-ethylbenzylamine were heated to reflux in 80 ml of ethanol for 3 hours. The solvent was evaporated from the reaction mixture, the residue was taken up in 2M hydrochloric acid and washed twice with methylene chloride. The aqueous layer was basified to about pH 12 with sodium carbonate and extracted with methylene chloride. The organic extract was dried over magnesium sulphate and evaporated to an oily residue which solidified upon trituration with dlisopropyl ether. The solid material was filtered off and discarded, and the filtrate was evaporated in vacuo to give the title compound as an oil (4.4 g).

1 H-NMR (CDCl 3): 7.2 (s, 5H), 7.05 (s, 4H), 3.6 (s, 2H), 2.95 (s, 3H), 70 (s, 4H); 2.40 (q, 2H); 1.1 (t, 3H).

(C) N-Ethyl-4-methanesulfonamidophenethylamine

CH ₃ SO ₂ N

HVPČ / C

CH ₂ CH ₃

NH

CS 271 489 B2

4.3 g (12.9 mmol) of N-benzyl-N-ethyl-4-methanesulfonamidophenethylamine in 50 ml of ethanol containing 0.5 g of 10% palladium on carbon are stirred for 5 hours in a hydrogen atomosphere at 344.7. kPa. The reaction mixture was filtered, evaporated and the residue triturated with ether. The title compound is obtained in a yield of 2.6 g, m.p. 125-128 ° C. @ 1 H-NMR (CDCl3): 7.06 (s, 4H), 4.9 (β, 2H), 2.86 (s, 2H), 2.8 (β, 2H), 2.65 (q, 2H); 1.05 (t, 3H).

Preparation 10 (A) N-Methyl-N- (3-methyl-5-nitrobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

1.66 g (7.3 mmol) of N-methyl-4-methanesulfonamidophenethylamine and 0.82 g (3.6 mmol) of 2-chloromethyl-3-methyl-5-nitrobenzofuran (see Preparation 5B) are taken up in 20 ml of ethanol 3. heated to reflux for hours. The solvent was evaporated and the residue was purified by silica gel column chromatography, first using a 4: 1 mixture of methylene chloride and hexane and then methylene chloride containing increasing amounts of methanol (from 0% to 5%) as eluents. The product containing fractions were combined, evaporated and the residue recrystallized from ethanol. Yield: 1.52 g, m.p. 124-124.5 ° C.

Analysis calculated for: ^{C N HH} 23 NN NO ° ^S: C, 57.5; H, 5.55; N, 10.1;

found: 57.7% C, 5.65% H. 10.0% N.

@ 1 H-NMR (CDCl3): 8.45 (d, 1H), 8.25 (dd, 1H), 7.5 (d, 1H), 7.2 (q, 4H), 3, Δ (з, 2H), 3.05 (s, 3H), 2.9 (t, 2H), 2.75 (t, 2H), 2.4 (s, 3H), 2.35 (s, 3H) ).

CS 271 489 B2 (V) N-Methyl-N- (3-methyl-5-aminobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

CH 2 SO 4 NH

0.7 g of the product prepared in Part (A) was catalytically hydrogenated for 4 hours in a manner analogous to Preparation 1C to give 0.65 g of the title compound. @ 1 H-NMR (CDCl3): 7.25. (m, 6H), 6.9 (d, 1H), 8.6 (dd, 1H),

3.8 (s, 2H), 2.95 (β, 3H), 2.9 (m, 2H), 2.7 (m, 2H), 2.4 (s, 3H), 2.35 (s , 3H).

Preparation 11 (A) N-Ethyl-N- (6-nitroquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine

and

H

1.7 g (7.0 mmol) of N-ethyl-4-methanesulfonamidophenethylamine (see Preparation 9C) and 0.78 g (4.1 mmol) of 2-chloromethyl-6-nitroquinoline are heated to boiling in 50 ml of ethanol for 4 hours. under reflux. The solvent was evaporated, the residue was diluted with an aqueous solution of hydrogen carbonate 271 489 B2 and extracted with methylene chloride. The organic layer was dried over magnesium sulphate, evaporated and the residue purified by chromatography on a silica gel column using methylene chloride as eluent. The product containing fractions were combined and evaporated to give 0.56 g of the title compound as an oil.

1 H-NMR (CDCl 3): 8.6 (d, 1H), 8.3-8.0 (m, 2H), 7.6 (d, 1H),

7.1 (9, 1H), 7.0 (9, 4H), 3.9 (9, 2H), 2.9 (9, 2H), 2.7 (9, 2H), 2.65 (q 2 H, 1.05 (t, 3H).

(Β) N-Ethyl-N- (6-aminoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine

H ₂ / Pd / C

0.55 g of the product prepared in Part (A) is catalytically hydrogenated in a similar manner to Preparation 1C8 by using hydrogen in the presence of 5% palladium on carbon catalyst, working in ethyl acetate and hydrogenating under pressure for 3 hours. 103.4 kPa. 0.51 g of the title compound is obtained.

@ 1 H-NMR (CDCl3): 7.7 (d, 1H), 7.5 (e, 1H), 7.15 (d, 1H), 6.9 (br, 5H), 6, 65 (d, 1H), 3.75 (e, 2H), 2.95 (β, 3H), 2.6 (s, 4H), 2.5 (q, 2H), 0.95 (t, 3H) ).

Preparation 12 (A) 6-Amino-2-methylquinoline

H ₂ / Pd / C

CS 271 489 82

18.8 g of 2-methyl-6-nitroquinoline in ethanolic solution in the presence of 5% palladium on carbon are stirred for 2 hours in a hydrogen atom at 20 psi. The catalyst is filtered off, the filtrate is evaporated to a small volume in vacuo, the precipitate formed is filtered off, washed with ethyl acetate and ether and dried to give 13.2 g of the title compound, m.p. 180-189 ° C.

Analysis for ^C io IQ ^H 2 ^N Calculated 75.9% C, 6.4% H, 17.7% N;

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

(B) 6-Methanesulfonamido-2-methylquinoline

CH ₃ SO ₂ C1 pyrrole

H

To a stirred solution of 12.5 9 6-amino-2-methylquinoline in 100 mL of pyridine cooled to 5 ° C was added dropwise 6.2 mL of methane sulfenyl chloride. The reaction mixture was stirred at room temperature for 17 hours, then the pyridine was evaporated in vacuo, the residue was diluted with aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give the title compound (13.0 g), m.p. 151-153 ° C.

For ^{C 11 H 12 N} 2 ^O 2 ^S calculated 55.9% Cm 5.1% H, 11.9% N;

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

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

NSO ₂ CH ₃ 'MCFBA

CS 271 489 B2

С ’

To a solution of 6 g of 6-methanesulfonaeido-2-methylquinoline in methylene chloride was added portionwise 5 * 2 g of m-chloroperbenzoic acid (MCPBA ^e ) * reaction mixture and stirred for 17 hours * then diluted with aqueous sodium bicarbonate solution and the organic layer separated. The aqueous layer was extracted with methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized from ethanol to give 1 * 6 g of the title compound, mp 241-243 ° C.

Analysis: ^ H ^H 12 ^N 2 ° 3 ^S Calculated% C, 52.4 * 4 * 8 * H% * 1 11% N;

found: 52.5% C, 4 * 95% H, 11 * 0% N.

(O) 2-Chloromethyl-6-methanesulfonaaidoquinoline

p-trifluoromethyl chloride

A mixture of 1 * 65 g of 6-methanesulfonamido-2-methylquinoline-1-oxide and 1 * 72 g of p-toluenesulfonyl chloride in a solution in 1,2-dichloroethane was heated under reflux for 1 hour. rooms. The reaction mixture was washed twice with aqueous sodium bicarbonate and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using methylene chloride containing increasing amounts of methanol (from 0% to 1%) as eluent. Product containing fractions were combined and evaporated to a gummy residue which solidified upon trituration with ether. Recrystallization from toluene gave the title compound (m.p. 160-162 ° C) in a yield of 0.75 g. Analysis calculated for ^C 11 ^H 11 W 3 ^S : C, 48.8; H, 4.1; N, 10.35. Found: C, 49.3; H, 3.9;

Preparation 1Э (A) 2-Chloro-thyl-5-nitrobenzo-thiophene

SOCl ₂ pyridine

To a stirred mixture of 1.0 9 5-nitrobenzo (b) -thiophan-2-methanol and 2 drops of pyridine in 10 ml of dichloromethane and 1.0 ml of thionyl chloride was added dropwise, and the resulting solution was stirred at room temperature for 4 hours. The residue is chromatographed on silica gel using dichloromethane as eluent to give a solid which, after crystallization from ethyl acetate, yields 0.73% of the title compound, m.p. which melts at 110 to 112 ° C and is directly used in the next reaction step.

(B) N-Methyl-N-ZB-nitro-2-benzo [b] thienylmethyl] -4-nitrophenethylamine

CS 271 489 82

A mixture of 3.20 g of the product prepared in part (A) above, 2.52 g of N-methyl-4-nitrophenethylamine, 4.0 g of anhydrous potassium carbonate and 40 ml of acetonitrile is stirred and refluxed for 20 hours, then is cooled and filtered. The residue on the filter was washed with acetonitrile, the filtrate was combined with 8 washings and evaporated to an oily residue which was chromatographed on silica gel. Product containing fractions were combined and evaporated to give the title compound (4.17 g), m.p. 76-78 ° C after isopropanol crystallization.

Analysis: ^{C H} I3 I7 3 ^N ° 4 ^S Calculated 58.2% C 4.6% H 11.3% Found 57.8 Nj% C, 4.4% H, 11.1% N

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

A mixture of 1.0 g of the product prepared in (V) above and 6.07 g of stannous chloride dihydrate in 100 ml of ethanol was heated at reflux for 8 hours and then evaporated. Excess 20% aqueous sodium hydroxide solution was added to the residue and the mixture was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to an oily residue which was chromatographed on silica gel. Elution with dichloromethane / methanol (99: 1) elutes the impurities, then eluting the column further with dichloromethane / methanol (98: 2). The appropriate fractions were combined and evaporated to give 0.30 g of an oleic product which was used immediately as in Example 6.

Preparation 14 (A) 4- [2- (Methanesulfonylxy) ethyl] methanesulfonanilide

CH3SO2Cl

CS 271 489 B2

CH ₂ CH ₂ OSO ₂ CH ₃

To a solution of 41.15 g of 4-aminophenethyl alcohol in 350 ml of pyridine, 50 ml of methanesulfonyl chloride was added dropwise at 0 ° C with stirring over 0.5 hours. The reaction mixture was allowed to warm to room temperature and stirred overnight. ml of water, a bronze-colored solid crystallizes. After filtration, this solid is dissolved in methylene chloride, dried over magnesium sulfate, filtered and evaporated again. The solid residue obtained after crystallization from ethyl acetate gives 45.5 g of the title compound. , melting point 136 to 137 ° C ·

Analysis: ^{С Н} 10 ° 15 * 2 5 ⁸ Calculated 40.9% C, 5.15% H, 4.8% N;

Found: 40.6% C, 5.2% H, 4.9% N. '(B) 4- / 2- (Methylamino) ethyl / methanesulfonanilide

CH ₂ CH ₂ SO ₂ CH ₃

CH ₃ SO ₂ NH

(CH 2 Cl 2)

To a solution of 10.3 g of 4- [2- (methanesulfonyloxy) -ethyl] methanesulfonanilide in 20 ml of ethanol is added 30 ml of a 33% methylamine solution in technical alcohol denatured with methanol. The mixture was heated in a pressure vessel at 85 ° C for 17 hours with stirring, then cooled, the resulting solution was evaporated to dryness, the residue was dissolved in water and the aqueous solution basified by adding a solution of 1.4 g of sodium hydroxide in 12 ml of water. Evaporation gave an off-white solid which was chromatographed on silica gel (Kieselgel 60 ^м ) using a 3: 1 mixture of methylene chloride and methanol.

The appropriate fractions were combined and evaporated to give 4.8 g of an off-white solid, which upon crystallization from ethyl acetate-methanol gave 1.8 g of the title compound, m.p. 133-135 ° C.

Analysis: calculated for ^C 16 ^H 16 ^N 2 ^O 2 ^S 52.6%, 7.1% H, 12.3% N;

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

Claims (6)

A process for the preparation of sulfonamide derivatives of alcylsulfonaaidophsnethylamines of the general formula I (I) in which alk represents an alkyl group having 1 to 4 carbon atoms, R ¹ represents an alkyl group having 1 to 4 carbon atoms and Het represents a radical of the formula R is hydrogen, methyl or ethyl, alk is as defined above, and X represents an oxygen atom, a sulfur atom or a NR ⁴ radical, wherein R ⁴ represents a hydrogen atom or a methyl group, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (V) (5) CS 271 489 B2 in which R ^a represents an amino group or a -NHSO ₂ alk radical wherein alk represents a C 1 -C 4 alkyl group, R ¹ represents an alkyl group having 1 to 4 carbon atoms and Het means a radical of the formula in which R and X are as defined above and R 6 represents an amino or -NHSC 1-4 alk group, where alk is as defined above, by limiting the fact that R 5 and R 5 are not simultaneously -NHSC 4 alk, reacts with an alkanesulfonyl chloride or a C 1 -C 4 -bromide or an anhydride alkanesulfonic acids having 1 to 4 carbon atoms, whereupon the resulting compound of formula (I) is optionally converted into its pharmaceutically acceptable salt. 2. The process of claim 1 wherein the DC reaction is carried out in the presence of an acid acceptor. 3. A process as claimed in any one of Claims 1 and 2, wherein the corresponding starting materials are used to form the compounds of formula I in which the alk is CH3, R ¹ represents a methyl or ethyl group and Het is a radical of formula or CS 271 489 B2 where Zněměná ^R2 is hydrogen or methyl, X represents an oxygen or sulfur atom; and R ³ which is attached at the a, or b position of the Het radical is -NHSO 5 CH 2. 4. A process according to claim 1, wherein the compound of formula IA (IA) is characterized in that ee N-methyl-N- ( 5-Aminobenzofur-2-ylmethyl) -4-aminophonethylamine reacts with methane sulfonyl chloride in the presence of an acid ecceptor 8. The process of claim 1 wherein N-methyl-N * (6-aminoquinol * 2-ylmethyl) -4-aminophenethylamine is reacted with methanesulfonyl chloride in the presence of a cyeeline acceptor. 6. A method according to claim 4 or 5, characterized in that pyridine is used as the eceeleptor of the cyeelines.