HU201743B - Process for producing sulfonamide derivatives with antiarrythmic effect and pharmaceutical compositions comprising same - Google Patents

Abstract

N-Heterocyclylmethyl- 2-phenethylamine derivs. of the formula (I) and their salts are new; where R = NHSO2 (1-4C) alkyl, NH2 or NO2; R1 = 1-4C alkyl; Het = (II), (III) or (IV); R2 = H, CH3 or Et; R3 = -NHSO2 (1-4C alkyl), -NH2 or -NO2; X = O, S or NR4; R4 = H or CH3. The proviso is when one of R and R3 is NO2 then the other is not NH2.

Description

The present invention relates to sulfonamide derivatives and to antiarrhythmic compositions containing such compounds.

European Patent Applications No. 164,697 A, French Patent Nos. 2,305,179 A and UK Patent Nos. 1,620,801 A disclose benzofuranylmethylamine and benzodioxanyl amine compounds, but these have no antiarrhythmic activity.

The compounds of the present invention have prolonged effects on the heart muscle and connective tissue and thus enhance resistance to early stimuli. Accordingly, these agents are classified according to Vaughan Williams Classification (Anti-Arrhythmic Action, Ε M. Vaughan Williams, Academic Press, 1980), Volume III. antiarrhythmics of Class. The compounds are active in vitro and in vivo in the atrium and the ventricles, as well as in the surrounding tissues, and are thus useful in the treatment of a variety of ventricular and ventricular diseases, including atrial and ventricular fibrillation. They do not have a greater tendency to induce or worsen arrhythmias than the known active substances (class I) and have less neurological side effects, without changing the heart rate. Some of the compounds obtained by the process of the invention also have positive ionotropic effects and are therefore particularly advantageous in patients with reduced cardiac pumping capacity.

The compounds of the present invention are represented by the following general formula (I)

R is -NHSO2 (C1-C4 alkyl),

R 'is C 1 -C 4 alkyl, and

Seven represents a group of formula (1 '), (2') or (3 ') in which

R ² is hydrogen, methyl or ethyl,

X is oxygen or sulfur.

The invention also relates to a process for the preparation of acid addition salts of the compounds of formula (I).

The -NHSO2-alkyl group is preferably in the 6- or 7-position when Sev is a quinolyl group and in the 5- or 6-position when Sev is another, i.e. a 5-membered benzene ring fused to the above heterocyclic group.

Preferred compounds of formula (I) are described by formulas (IA) and (IB).

Salts of compounds of formula I are acid addition salts prepared with pharmaceutically acceptable acids or compounds containing such anions. For example, hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, benzylate or p-toluenesulfonate. The salts are prepared according to known procedures.

The effect of the compounds of the present invention on atrial resistance was investigated in the right atrium of a guinea pig immersed in physiological saline and connected to a force transducer at one end. The tissues were stimulated at a frequency of 1 Hz. An effective refractory period (ERP) with the introduction of S2 early (premature) stimuli,

Measured after base stimulus 8 (Si). The switching interval S1S2 is incrementally increased until S2 re2 is capable of eliciting an increasing response. This is characterized by the ERR At this point, determine the drug concentration required to increase the ERP by 25% (ED25). ERP values were also measured on the right papillary muscle of guinea pigs incubated in physiological saline. Muscles were stimulated with bipolar electrodes at one end and the electrogram was recorded with a unipolar surface electrode at the other end. The ERP was determined by the extrastimulus procedure described above. Conduction time was determined using a digital storage oscilloscope, measuring the interval between the artificially induced effect and the peak of the electrogram, i.e. the time required to transmit the pulse over the entire length of the muscle.

The atrial and ventricular ERP values were also examined in anesthetized and alert dogs using the above extrastimulus method, while the pacemaker and right ventricular were continuously stimulated.

The compounds of formula I obtained by the process of the present invention may be administered alone or in the form of their pharmaceutical compositions. According to the process of the present invention, the pharmaceutical compositions are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and / or excipient (s) and making them suitable for administration to a pharmaceutical composition. These compositions are used to treat or prevent arrhythmic disorders.

The pharmaceutical compositions of the present invention may be administered orally in the form of tablets, capsules, elixirs or suspensions, or parenterally, e.g., intravenously, intramuscularly or subcutaneously. Tablet formulations may contain, for example, starch or lactose, the capsules may contain the active ingredient alone or in combination with other additives, and elixirs or suspensions may contain flavoring and / or coloring agents. Formulations for parenteral administration are usually prepared in the form of sterile aqueous solutions which may contain other solutes, such as glucose salts, for example for the adjustment of isotope.

The active compounds of the formula I are administered orally to adult patients (~ 70 kg) in doses of 2-150 mg / day in four divided doses. For intravenous administration, the dose is 1-20 mg. For severe cardiac arrhythmias, it is preferred

arc. dosage to achieve a rapid effect. Oral formulations generally contain from 2 to 50 mg of active ingredient along with the carrier. The above dosages may vary with the weight of the patients and the severity of the disease.

In the process of the present invention, the compounds of formula I are prepared as follows:

1) In one method, compounds of formula B wherein R ^a is NHSO 2 (C 1 -C 4 alkyl) - or -NH 2 and Sev is of formula (1 "), (2") or (3 ") wherein R ² and X are as defined above and R ^b is -NH 2 - or -NHSO 2 - (C 1 -C 4 alkyl) - are acylated with C 1 -C 4 alkanesulfonic acid chloride or bromide or C 1 -C 4 alkanesulfonic anhydride. If R ^a and R ^{b are} present-21

If both NH2 groups are used, obviously two equivalents of reagents will be used and the two substituents will have the same meaning in the final product.

The reaction is generally carried out at room temperature, optionally in the presence of an acid scavenger such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The acid acceptor is particularly necessary when alkanesulfonic acid chloride or bromide is used. The reaction is particularly preferably carried out with alkanesulfonic acid chloride in the presence of pyridine. The compounds of formula (I) obtained are isolated in known manner.

The starting compounds for the acylation reaction are prepared according to Schemes A and B. In the schemes, R, Sev is as defined above, Q is a leaving group such as chlorine, bromine or iodine or methanesulfonyloxy. Alternatively, starting from compounds which have a nitro group on the Sev group instead of a C 1-4 alkanesulfonamido group, the dinitro intermediate can be converted to the corresponding starting compound by catalytic hydrogenation. The starting compounds may also be prepared by the reaction scheme Scheme C. In the above formulas, R is C 1-4 alkyl, the Sev group is a nitro-substituted heterocyclic group as defined above, and Q is one of the above leaving groups.

The compounds obtained according to the methods described above are known or can be prepared by known methods.

2. Another embodiment of the process of the invention is illustrated in Schemes D and E. In the scheme, R ¹ is C 1-4 alkyl, Sev is as defined above, Q is a leaving group, preferably chloro, bromo or iodo, C 1-4 alkanesulfonyloxy, preferably methanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy group. The reaction is usually carried out in the presence of an organic solvent, and the reaction temperature is up to max. the reflux temperature of the solvent. The reaction is preferably carried out under reflux. Optionally, an acid acceptor may be used, especially when Q is chlorine, bromine or iodine. Preferably the acid scavenger is pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The starting compounds used are known or can be prepared in a known manner.

The following Examples further illustrate the process of the invention.

Example 1

N-Methyl-N- (3-methyl-5-methanesulfonamido-benzofur-2-ylmethyl) -4-methanesulfonamido-phenethylamine (Scheme 1)

Methanesulfonyl chloride (0.21 g, 1.85 mmol) was added dropwise to N-methyl-N- (3-methyl-5-aminobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine in pyridine (7 mL) (see starting material 10B). (0.78 g, 1.68 mmol) was added and the solution was stirred at room temperature for 60 hours, the solvent was evaporated and the residue was stirred with toluene. The toluene is then decanted, the residue is stirred with aqueous sodium bicarbonate, the precipitate is filtered off and recrystallized from methanol to give 0.38 g of the title compound.

M.p. 142-143,5'C.

Elemental analysis for C21H27N3O5S2,%.

Found: C-54.4, H-5.8, N-9.1; Calc'd: 0 = 54.2, H = 5.85, N = 9.0.

Example 2

N'Methyl-N- (5-methanesulfonamido-benzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 2)

Methanesulfonyl chloride (0.76 g, 6.6 mmol) was added to N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (25 mL) in pyridine (Preparation 3, 0.9). g, 3.0 mmol) was added, the mixture was stirred at room temperature for 18 hours, the solvent was evaporated, and the residue was diluted with aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The organic extracts were combined, dried over magnesium sulfate, concentrated and the residue chromatographed on silica gel (ethyl acetate). The product-containing fractions were combined, concentrated and the residue was recrystallized from ethyl acetate / methanol to give 0.35 g of the title compound.

Mp: 177-179 ° C.

Elemental analysis for C20H25N3O5S2,%:

Found: C-53.2, H = 5.7, N-9.0; Calc'd: C-53.2, H-5.6, N-9.3.

Example 3

N-Methyl-N- (5-methanesulfonamido-benzoxazol-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 3)

Methanesulfonyl chloride (0.38 g, 3.3 mmol) was added to N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (20 mL) in pyridine (Preparation IC, 0, 45 g, 1.5 mmol) and a

The reaction was carried out as described in Example 2. Recrystallization from ethanol gave 0.25 g of the title compound.

Mp: 174-176 ° C.

Elemental analysis for C19H24N4O5S2,%:

Found: C-50.4, H = 5.1, N-12.4; Calc'd: C, 50.4; H, 5.35; N, 12.4.

Example 4

N-Methyl-N- (6-methanesulfonamido-benzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 4)

Methanesulfonyl chloride (0.21 g, 1.8 mmol) in N-methyl-N- (6-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (3 mL) in pyridine (Preparation Example 2) (0.24 g, 0.82 mmol) was added followed by a

Example 2 was followed. 0.18 g of the title compound is obtained in the form of an oil.

Elemental Analysis for: C 20 H 25 N 3 O 5 S 2 Found: C-53.0, H-5.7, N-9.1; Calc'd: C-53.2, H-5.6, N-9.3.

HU 201743 Β

Example 5

N-Methyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 5)

Methanesulfonyl chloride (0.15 g, 1.3 mmol) was added to N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethylamine (20 mL) in pyridine (Preparation 4) (0.17 g, 0.37 mmol) was added followed by the procedure of Example 2. Recrystallization from ethyl acetate gave 0.70 g of the title compound.

M.p. 163-165 ° C.

Elemental analysis for C21H26N4O4S,%:

Found: C-54.3, H = 5.45, N-12.1; H, 5.7; N, 12.1. Found: C, 54.5;

Example 6

N-Methyl-N- [5-methanesulfonamido-2-benzo [b] thienylmethyl] -4-methanesulfonamido-phenethylamine (Scheme 6)

0.23 g of methanesulfonyl chloride and 0.26 g of N-methyl-N- (5-amino-2-benzo [b] thienylmethyl) -4-aminophenethylamine (starting material 13, Preparation Example) in pyridine solution are obtained as follows. The reaction was carried out as described in Example 1b. 0.167 g of the title compound are obtained.

Mp: 175-177 ° C.

Elemental Analysis for: C20H25N3O4S3: C, 50.99; H, 5.39; N, 8.93; H, 5.39; N, 8.99 Found: C, 51.37;

Example 7

N-Ethyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4-methanesulfonamido-phenethylamine hydrochloride (Scheme 7)

Methanesulfonyl chloride (0.1 g, 1.29 mmol) and N-ethyl-N- (6-aminoquinol-2-ylmethyl) -4 (0.51 g, 1.23 mmol, Example 11B) -methanesulfonamido-phenethylamine in pyridine solution was reacted as described in Example 2. The resulting gum was the free base of the title compound, which was dissolved in ethyl acetate, diluted with ethereal hydrochloric acid and evaporated to dryness. The residue was stirred with ether to give the title compound as a foam, 0.06 g.

Mp .: 96 'C.

Elemental analysis for C22H28N4O4S2.HCl.H2O,%:

Found: C-50.2, H-5.5, N-10.0; H, 5.9; N, 10.5.

Example 8

N- (6-Methanesulfonamido-2-quinolylmethyl) -N-methyl-4-methanesulfonamido-phenethylamine (Scheme 8)

0.228 g (1 mmol) of 4- [2- (methylamino) ethyl] methanesulfonanilide (Preparation Example 14B) and 0.135 g (0.5 mmol) of 2-chloromethyl-6-methanesulfonamidoquinoline (m.p. Example 12D Preparation of starting material) (5 ml) in ethanol was heated at reflux for 4 hours, then the solvent was evaporated in vacuo to give a residue. The material was dissolved in methylene chloride, washed with water, dried, filtered and concentrated in vacuo. The resulting gum was chromatographed on silica gel (methylene chloride, 0-1% methanol). The product-containing fractions were combined and concentrated in vacuo to give a foam-like material which was recrystallized from ethanol to give the title compound (0.45 g).

165-166 ° C, spectroscopic, identical to the compound of Example 5.

The following Examples illustrate the process for preparing the new starting materials.

Preparation of starting materials

Example 1 (A) 2- (Chloromethyl) -5-nitrobenzoxazole (Scheme 9) g (65 mmol) of 2-amino-4-nitrophenol and 15.4 g (97.5 mmol) of ethyl The chloroacetimidate hydrochloride was heated under reflux in ethanol (100 mL) for 18 hours. The solvent was evaporated in vacuo and the residue was recrystallized from ethanol. 9 g of the title compound are obtained.

216-217 'C.

Elemental analysis for C8H5ClN2O3,%.

Found: 045.15, H-2.3, N-13.25; Calc'd: 045.2, H-2.4, N = 13.2.

(B) N-Methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine (Scheme 10)

2.85 g (13.4 mmol) of 2- (chloromethyl) -5-nitrobenzoxazole and 2.2 g (12.2 mmol) of N-methyl-4-nitrophenethylamine (JOC, [1956] 21, 45) In the presence of 1.85 g (13.4 mmol) of potassium carbonate and 2.0 g (13.4 mmol) of sodium iodide in 50 mL of acetonitrile was heated at reflux for 3 days. The solvent was evaporated, the residue was diluted with water, extracted three times with methylene chloride, the organic extracts were combined, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The oily residue was diluted with ether, the supernatant decanted and evaporated to dryness to give an orange solid which was recrystallized from isopropanol to give the title compound (0.8 g).

1 H-NMR (CDCl 3): = 8.6 (d, 1H), 8.3 (dd, 1H),

8.1 (d, 2H), 7.6 (d, 1H), 7.35 (d, 2H), 3.95 (s, 2H), 2.95 (q, 2H), 2.85 (q , 2H), 2.5 (s, 3H) ppm.

(C) N-Methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (Scheme 11)

0.78 g (2.2 mmol) of N-methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine in 50 ml of ethanol containing 0.1 g of Raney nickel in a hydrogen atmosphere. After stirring for 18 hours (344.7 kPa), TLC showed complete consumption of the starting material (silica gel plate, methylene chloride / methanol 19: 1), filtered and evaporated. The residual oil, which is an azeotropic toluene mixture, is mixed with ether, the ether is removed by decantation, and the product is concentrated to give 0.45 g of the title compound as an oil which is used directly for the reaction.

HU 201743 1 H-NMR (CDCl 3): -7.25 (d, 1H), 6.95 (dd, 3H),

6.65 (dd, 1H), 6.6 (d, 2H), 3.85 (s, 2H), 2.7 (s, 4H),

2.4 (s, 3H).

2-4. Examples 5

The compounds of Examples 2 and 3 were prepared by IC. Prepared similarly to Example 1B using the appropriate dinitro compound (Preparation Examples 6 and 5) and H2 / Raney nickel / ethanol / 344.7 kPa / room temperature for 4 and 17 hours, respectively. Preparation 4 was carried out as in Example 1C, but the reaction conditions were: H2 / Pd / C in ethanol and at -229 kPa for 3 hours. The corresponding dinitro compounds were prepared as in Example 8. (Scheme 12)

Example number for the preparation -Het'-NO2 -Het'-NH2 'H-N.m.r.

δ (CDCl 3) = 7.25 (d, 1H);

6.95 (d, 2H); 6.75 (s, 1H);

6.65 (s, 1H); 6.6 (d, 2H);

6.4 (s, 1H); 3.65 (s, 2H); 2.6 (m. 4H); 2.3 (s, 3H).

δ (DMSO / TFA) = 7.75 (d, 2H); 7.3 (m. 5H); 4.7 (d, 2H); 3.4 (q, 4H); 2.85 (s, 3H).

Example 5 (A) 4- (Isopropylidene-amine-oxypnitrobenzene (Scheme 13)) Propanone oxime (0.4 mol) in tetrahydrofuran (300 ml) was slowly dissolved in sodium hydride (10.8 g, 0.45 mol). When the evolution of gas has completely ceased, 100 ml of dimethyl sulfoxide and 57.85 g (0.41 mol) of 4-fluoronitrobenzene are added to the reaction mixture and the mixture is stirred for 2 hours at room temperature. Extract three times with ether, combine the extracts, wash with water, dry over magnesium sulfate and concentrate to obtain the title compound, which is mixed with hexane and filtered to give 67 g, of which 7 g is recrystallized from ethanol. win.

104-106 'C.

Elemental Analysis for: C9H10N2O3%: Found: C-55.6, H-5.05, N-14.35; Calc'd: C, 55.7; H, 5.2; N, 14.4.

(B) 2-Methyl-5-nitrobenzofuran (Scheme 14) g (0.309 mol) of 4- (isopropylideneaminyloxy) -nitrobenzene was added to 530 ml of glacial acetic acid containing 25 g of gaseous hydrochloric acid and the resulting mixture Stir at 100 ° C for 18 hours. The solvent was removed and the residue was azeotroped with cyclohexane to give an oily substance which was diluted with water and extracted three times with methylene chloride. The organic extracts were combined, washed with 10% aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated to give 46 g of the title compound. Recrystallization of 5 g from isopropanol yields 2.5 g of pure material.

Mp: 93-95 ° C.

Elemental Analysis for: C9H7NO3,%: Found: C-61.2; H-4.1; N-7.9; Calc'd: C-61.0, H = 4.0, N = 7.9 (C) 2-Bromomethyl-5-nitrobenzofuran (Scheme 15)

N-Bromosuccinimide (1.1 g, 6.2 mmol) was added in small portions to 1 g (5.6 mmol) of 2-methyl-5-nitrobenzofuran in 50 ml of carbon tetrachloride and 50 mg of benzoyl peroxide was added. heat to reflux for 6 hours, then cool, filter and evaporate the filtrate to dryness. The residue was obtained from petroleum ether (0.75 g).

96-98 'C.

Elemental Analysis for: C9H8BrNO3,%: Found: C-41.7, H-2.4, N-5.3; Calculated: C-42.2, H-2.4, N-5.5.

(D) N-Methyl-N- (5-nitrobenzofur-2-ylmethyl) -4-nitrophenethylamine (Scheme 15a)

N-methyl-4-nitrophenethylamine (0.41 g, 2.3 mmol); 2-bromomethyl-5-nitrobenzofuran (0.66 g, 2.6 mmol); Sodium iodide (6 mmol) and potassium carbonate (0.36 g, 2.6 mmol) in acetonitrile (50 mL) were heated at reflux for 8 days, then the solvent was evaporated, water was added to the residue and extracted three times with methylene chloride. The organic extracts were combined, washed with water, dried over magnesium sulfate, and concentrated to give a residue which was recrystallized from isopropanol to give the title compound (380 mg).

HU 201743 1 H-NMR (DMSO / TFA): -8.75 (s, 1H), 8.3 (d, 1H), 8.2 (d, 2H), 7.9 (d, 1H), 7.6 (d, 2H), 7.45 (s, 1H), 5.74 (t, 2H), 3.2 (t, 2H), 2.9 (s, 2H), 2.5 (s) , 3H).

Example 6 (A) 2-Bromomethyl-6-nitrobenzofuran (Scheme 16)

1.11 g (6.2 mmol) of N-bromosuccinimide ("NBS") were treated with 20 mg of azo-bis (isobutyronitrile) and 1 g (5.65 mmol) of 2-methyl-6-nitrobenzofuran carbon. to a solution of tetrahydrochloride was added under reflux

After stirring for 1.5 hours, the solvent was evaporated and the residue was dissolved in methylene chloride, washed with water, dried over magnesium sulfate, evaporated to dryness and chromatographed on silica gel (methylene chloride / hexane = 7: 3). The product-containing fractions were combined and concentrated to give the title compound (1.43 g). According to 1 H NMR, this product contains 20% 2-dibromomethyl-6-nitrobenzofuran, but it is not necessary to remove it as it is suitable for further reaction directly without purification.

(B) N-Methyl-N- (6-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine (Scheme 16a)

0.84 g (4.7 mmol) of N-methyl-4-nitrophenethylamine,

1.2 g (4.7 mmol) of 2-bromomethyl-6-nitrobenzofuran, 0.7 g (4.7 mmol) of sodium iodide and 0.71 g (5.2 mmol) of potassium carbonate in acetonitrile After refluxing for 18 hours, the reaction mixture was cooled, filtered, the filtrate was concentrated and the residue was chromatographed on silica gel (methylene chloride / hexane 1: 1 and then methylene chloride / methanol 19: 1). concentrated, the residue was decolorized with activated charcoal in ethanol and the oily residue solidified on standing. Recrystallization gave the title compound (0.27 g).

M.p. 69-69.5 'C.

Elemental Analysis for: C18H17N3O5,% C, 60.8; H, 4.8; N, 11.8; H, 4.8; N, 11.8.

1 H-NMR (CDCl 3): = 8.3 (s, 1H), 8.15 (dd, 1H),

8.1 (d, 2H), 7.55 (d, 1H), 7.35 (d, 2H), 6.65 (s, 1H), 3.8 (s, 2H), 3.95 (t , 3H), 2.75 (t, 3H), 2.4 (s, 3H).

Example 7 (A) 2- (Hydroxymethyl) -3-methyl-5-nitrobenzofuran (Scheme 17) A solution of diborane in 1 M tetrahydrofuran (18.0 mmol) was suspended in tetrahydrofuran (0 g) at 0 ° C. (5 mmol) was added to 3-methyl-5-nitrobenzofuran-2-carboxylic acid at 0 ° C, stirred at this temperature for 30 minutes and then at room temperature for 18 hours, and a second solution of diborane (5 ml) was added. The reaction mixture was then sonicated for 2.5 hours, then methanol was carefully added and the solvent was evaporated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, the solvent evaporated in vacuo and the residue 6 chromatographed on silica gel (methylene chloride). The product-containing fractions were combined and concentrated to give 0.96 g of the title compound.

149-150 ° C (after recrystallization from ethyl acetate).

Elemental analysis for C10H9NO4. %: Found: C-57.9, H-4.2, N = 6.7; Calculated: C, 58.0; H, 4.4; N, 6.8.

(B) 2- (Chloromethyl) -3-methyl-5-nitrobenzofuran (Scheme 18)

Thionyl chloride (1.48 g, 12.4 mmol) was added in small portions to 2- (hydroxymethyl) -3-methyl-0.86 g (4.15 mmol) in methylene chloride (10 mL) containing 2 drops of pyridine. 5-nitrobenzofuran, the mixture was stirred at room temperature for 24 hours, then diluted with water, the organic phase was separated, the aqueous phase was repeatedly extracted with methylene chloride, the organic phases were combined, washed with aqueous sodium bicarbonate and dried over sodium sulfate. and evaporating the solvent. 0.93 g of the expected product is obtained, which is recrystallized from ethanol.

M.p. 141-142 'C.

Elemental Analysis for: C10H8CINO3,%: Found: C-52.95, H-3.7, N-6.0; Calc'd: C, 53.2; H, 3.6; N, 6.2.

Example 8

N-Methyl-N- (6-nitroquinol-2-ylmethyl) -4-nitro-phenethylamine (Scheme 19)

N-methyl-4-nitrophenethylamine (0.39 g, 2.15 mmol) and 2- (chloromethyl) -6-nitroquinoline (0.40 g, 2.1 mmol) in ethanol (30 mL) were refluxed for 6 hours. The solvent is evaporated, the residue is diluted with 2M hydrochloric acid, extracted with methylene chloride, the aqueous phase is made basic with aqueous sodium carbonate (pH = 12) and extracted three times with methylene chloride. The latter organic extracts were combined, dried over magnesium sulfate, concentrated, and the resulting oily substance was chromatographed on silica gel (methylene chloride containing 0-1% methanol), and the product-containing fractions were combined and concentrated. The resulting solid was recrystallized from ethanol to give the title compound (0.21 g).

104-105 ° C.

Elemental Analysis for: C19H18N4O4%: Found: C, 62.4; H, 4.7; N, 15.2; H, 4.95; N, 15.3.

1 H-NMR (CDCl 3): - 8.9 (d, 1H), 8.5 (dd, 1H),

8.3-8.1 (m, 3H), 7.6 (d, 1H), 7.35 (d, 1H), 3.95 (s, 2H), 3.0 (t, 2H), 2 , Δ (t, 2H), 2.4 (s, 3H).

Example 9 (A) 4-Methanesulfonamido-phenethyl mesylate (Scheme 20)

Methanesulfonyl chloride (146.6 g, 1.28 mol) was added dropwise to 4-aminophenethyl alcohol (82.3 g, 0.6 mol) in pyridine (700 ml), stirred at room temperature for 18 hours and then poured into water (700 ml). the precipitate was filtered off, washed with water, dried and recrystallized from ethyl acetate.

HU 201743 Β

31 g of the expected product are obtained.

134-136 ° C.

An additional 14.5 g of product was obtained by concentrating the mother liquor in vacuo.

(B) N-Benzyl-N-ethyl-4-methanesulfonamido-phenethylamine (Scheme 21) g (34 mmol) of 4-methanesulfonamido-phenethyl mesylate and 10 mL (67 mmol) of N-ethylbenzylamine in 80 mL of ethanol After heating for 3 hours at reflux, the solvent was evaporated, the residue was dissolved in 2M hydrochloric acid, washed twice with methylene chloride, basified with aqueous sodium bicarbonate (pH about 12) and extracted with methylene chloride. The latter organic extract was dried over magnesium sulfate and concentrated, and the resulting oily material was solidified by stirring with diisopropyl ether, the solid filtered, discarded, and the filtrate concentrated 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), 2.70 (s, 4H), 2.40 (q, 2H),

1.1 (t, 3H).

(C) N-Ethyl-4-methanesulfonamido-phenethylamine (Scheme 22)

N-Benzyl-N-ethyl-4-methanesulfonamidophenethylamine (4.3 g, 12.9 mmol) was stirred in hydrogen (50 mL) for 5 h under a hydrogen atmosphere of 344.7 kPa, 0.5 g of 10% palladium on carbon catalyst presence. The mixture was then filtered, concentrated and the residue was mixed with ether to give 2.6 g of the title compound.

Mp: 125-128 ° C.

1 H-NMR (CDCl 3 / DMSO): - 7.06 (s, 4H), 4.9 (s, 2H), 2.86 (s, 2H), 2.8 (s, 2H), 2.65 (q, 2H), 1.05 (t, 3H).

Example 10 (A) N-Methyl- (3-methyl-5-nitrobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 23)

N-Methyl-4-methanesulfonamidophenethylamine (1.66 g, 7.3 mmol) and 2- (chloromethyl) -3-methyl-5-nitrobenzofuran (0.82 g, 3.6 mmol) (starting material preparation example) 7B) Reflux in ethanol (20 ml) for 3 hours. The solvent was evaporated and the residue was chromatographed on silica gel (methylene chloride / hexane 4: 1 followed by methylene chloride containing 0-5% methanol), the product-containing fractions were combined, concentrated and the residue was recrystallized from ethanol. This gave 1.2 g of the title compound.

Mp 124-124,5 'C.

Elemental analysis for C20H23N3O5S,%:

Found: C-57.7, H-5.65, N-10.0; Calculated: C-57.5, H-5.55, N-10.1.

1 H-NMR (CDCl 3): - 8.45 (d, 1H), 8.25 (dd, 1H),

7.5 (d, 1H), 7.2 (q, 4H), 3.8 (s, 2H), 3.05 (s, 3H), 2.9 (t, 2H), 2.75 (t , 2H), 2.4 (s, 3H), 2.35 (s, 3H).

(B) N-Methyl-N- (3-methyl-5-aminobenzophir-2-ylmethyl) -4-melanesulfonamidophenethylamine (Scheme 24)

The product (0.7 g) from the previous step (A) was catalytically hydrogenated as described in Example 1C for 4 hours to give 0.65 g of the title compound.

1 H-NMR (CD 3 OD): - 7.25 (m, 6H), 6.9 (d, 1H), 6.8 (dd, 1H), 3.8 (s, 2H), 2.95 (s) , 3H), 2.9 (m, 2H),

2.7 (m, 2H), 2.4 (s, 3H), 2.35 (s, 3H).

Example 11 (A) N-Ethyl-N- (6-nitroquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 25)

1.7 g (7 mmol) of N-ethyl-4-methanesulfonamidophenethylamine (Example 9C) and 0.78 g (4.1 mmol) of 2-chloromethyl-6-nitroquinoline in 50 ml of ethanol for 4 hours The solvent is evaporated, the residue is diluted with aqueous sodium bicarbonate, the residue is extracted with methylene chloride, the organic phase is dried over magnesium sulfate, concentrated and the residue is chromatographed on silica gel with methylene chloride. The product-containing fractions were combined and concentrated to give 0.56 g of the title compound as an oily substance.

1 H-NMR (CDCl 3): - 8.6 (d, 1H), 8.3-8.0 (m, 2H), 7.6 (d, 1H), 7.1 (s, 1H), δ , 0 (s, 4H), 3.9 (s, 2H), 2.9 (s, 2H), 2.7 (s, 2H), 2.65 (q, 2H), 1.05 (t, 3H).

(B) N-Ethyl-N- (6-aminoquinol-2-ylmethyl) -4-methanesulfonamidophenethylamine (Scheme 26)

0.55 g of the product of the above A) is catalytically hydrogenated according to Preparation Example 1C), except that 5% palladium on carbon is used in ethyl acetate, the hydrogen pressure is 103.4 kPa and the reaction time is 3 hours. . 0.51 g of the title compound is obtained.

1 H-NMR (CDCl 3): - 7.7 (d, 1H), 7.5 (d, 1H), 7.15 (d, 1H), 6.9 (bs, 5H), 6.65 ( d, 1H), 3.75 (s, 2H), 2.95 (s, 3H), 2.6 (s, 4H), 2.5 (q, 2H), 0.95 (t, 3H).

Example 12 (A) 6-Amino-2-methylquinoline (Scheme 27)

18.8 g of 2-methyl-6-nitroquinoline are stirred under a hydrogen pressure of 206.8 kPa for 2 hours in a 5% palladium-on-carbon catalyst, the catalyst is filtered off, the filtrate is concentrated and the residue is filtered off washed with ethanol and ether and dried to give 13.2 g of the title compound.

M.p .: 188-198 'C.

Elemental Analysis for: C10H10N2% Found: C-75.7, H-6.4, N-17.6; Calculated: C-75.9, H-6.4, N-17.7.

(B) 6-Methanesulfonarnido-2-methylquinoline (Scheme 28)

Methylsulfonyl chloride (6.2 ml) was added dropwise to 12.5 g of 6-amino-2-methylquinoline in pyridine (100 ml) at 5 ° C.

After stirring at room temperature for 17 hours, the pyridine was evaporated in vacuo, the residue was diluted with aqueous sodium bicarbonate, extracted three times with methylene chloride, and the organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give a crude product. win.

Mp: 151-153 ° C.

For C11H12N2O2S: C, 55.4; H, 5.2; N, 11.6. Calc'd: C, 55.9; H, 5.1; N, 11.9.

(C) 6-Methanesulfonamido-2-methylquinoline-1-oxide (Scheme 29)

5.2 g of m-chloroperbenzoic acid ("MCPBA") are added in small portions to 6 g of 6-methanesulfonamido-2-methylquinoline in methylene chloride and the reaction mixture is stirred for 17 hours. The reaction mixture was diluted with aqueous sodium bicarbonate, the organic phase was separated, the aqueous phase was extracted with methylene chloride, the organic phases were combined, washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give a solid. 1.6 g of the title compound are obtained.

Mp: 241-243 'C.

Elemental analysis for C11H12N2O3S,%:

Found: C-52.5, H-4.95, N-11.0; H, 4.8; N, 11.1.

(D) 2- (Chloromethyl) -6-methanesulfonamidoquinoline (Scheme 30)

6-Methanesulfonamido-2-methylquinoline-1-oxide (1.65 g) and p-toluenesulfonyl chloride (1.72 g) were heated at reflux in 1,2-dichloroethane for 1 hour and then allowed to stand at room temperature for 17 hours. The mixture was then washed twice with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (methylene chloride containing 0-1% methanol), the product-containing fractions are combined, concentrated and the residue is solidified by mixing with ether. After recrystallization, 0.75 g of the title compound is obtained.

Mp: 160-162 ° C.

Elemental analysis for C11H11N2O2CIS,%:

Found: C-49.3, H-3.9, N-10.1; Calc'd: C, 48.8; H, 4.1; N, 10.35.

Example 13 (A) 2- (Chloromethyl) -5-nitrobenzo [b] thiophene (Scheme 31) 1 g of thionyl chloride dissolved in 10 ml of dichloromethane and 2 drops of pyridine were added under stirring. Add 2- (hydroxymethyl-5-nitrobenzo [b] thiophene), stir the resulting solution for 4 hours at room temperature, wash with water, aqueous sodium bicarbonate and dry over sodium sulfate. The solvent is evaporated and the residue is chromatographed on silica gel. methane), the resulting solid was recrystallized from ethyl acetate to give 0.73 g of the title compound.

Mp 110-112 ° C.

This product was used directly for the next reaction step.

(B) N-Methyl-N- [5-nitro-2-benzo [b] thienylmethyl) -4-nitrophenethylamine (Scheme 32)

3.2 g of the product obtained in A above are mixed with 2.52 g of N-methyl-4-nitrophenethylamine, 4 g of anhydrous potassium carbonate and 40 ml of acetonitrile, and the mixture is stirred at reflux for 20 hours and then cooled. and filter. The residue was washed with acetonitrile, the filtrate and the washings were combined, concentrated and the resulting oily substance was chromatographed on silica gel. Elution is carried out with dichloromethane to elute the impurity first and then to the pure product. The product-containing fractions were concentrated to give 4.17 g of the title compound.

76-78 ° C (recrystallized from isopropanol).

Elemental Analysis for: C18H17N3O4S Found: C, 57.8; H, 4.4; N, 11.1; Calc'd: C, 58.2; H, 4.6; N, 11.3.

(C) N-Methyl-N- [5-amino-2-benzo [b] thienylmethyl] -4-aminophenethylamine (Scheme 33)

1.0 g of the product obtained in (B) above is mixed with 6.7 g of stannous chloride dihydrate in 100 ml of ethanol and heated under reflux for 8 hours. The reaction mixture was concentrated, an excess of 20% sodium hydroxide solution was added, the mixture was extracted several times with dichloromethane, the organic extracts were combined, washed with water, dried over sodium sulfate, and concentrated to an oil which was chromatographed on silica gel. . Elution is carried out with 99: 1 dichloromethane / methanol to remove impurities first, followed by elution with 98: 2 dichloromethane / methanol to give product containing fractions. These were combined and concentrated to give 0.30 g of product as an oily substance which was used directly for Preparation Example 6.

Example 14 (A) 4- [2- (Methanesulfonyloxy) ethyl] methanesulfonanilide (Scheme 34): Methanesulfonyl chloride (mL) was added dropwise to 41.15 g of 4-aminophenethyl alcohol in 350 mL of pyridine over 0.5 h. at 0 ° C, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was then poured into water (700 mL), the crystalline orange solid was filtered off, dissolved in methylene chloride, dried over magnesium sulfate, filtered and the filtrate was concentrated again. After recrystallization (ethyl acetate), 45.5 g of the title compound are obtained.

Mp: 136-137 ° C.

Elemental analysis for C10H15NO5S2,%:

Found: C-40.6, H-5.2, N-4.9; Calc'd: C-40.9, H-5.15, N-4.8.

(B) 4- [2- (Methylamino) ethyl] methanesulfonanilide (Scheme 35)

Dissolve 10.3 g of 4- [2- (methanesulfonyloxy) ethyl] methanesulfonanilide in 20 ml of ethanol, add 30 ml (33% solution) of methylamine in industrial methyl alcohol and press at 85 ° C. under stirring for 17 hours. After cooling, the resulting solution is evaporated to dryness, the residue is dissolved in water, the resulting solution is made basic with 1.4 g of sodium hydroxide solution in 12 ml of water, concentrated and the resulting off-white solid is chromatographed on silica gel (Kieselgel 60). 1: 1). The appropriate fractions were combined and concentrated to give 4.8 g of a solid which was recrystallized from ethyl acetate / methanol to give 1.8 g of the title compound.

133-135 ° C.

Elemental Analysis for: C 10 H 16 N 2 O 2: Found: C-52.5, H = 7.1, N-12.2; Calc'd: C-52.6, H-7.1, N-12.3.

Claims (8)

A process for the preparation of a compound of formula (I) and an acid addition thereof R is -NHSO2 (C1-C4 alkyl) R ⁷ is C 1 -C 4 alkyl, Seven represents a group of formula (1 '), (2') or (3 '), wherein R ² is hydrogen, methyl or ethyl, X is oxygen or sulfur, characterized in that a) a compound of formula B wherein R _a is -NH 2 or -NHSO 2 (C 1 -C 4 alkyl), R 1 is C 1 -C 4 alkyl, and Sev is (1), (2 ') or ( 3 ") wherein R ² and X are as defined above, R ^b is -NH 2 or -NHSO 2 (C 14 alkyl), with the proviso that R ^a and R ^{b are} not simultaneously -NHSO 2 (1- C 4 alkyl, C 1 -C 4 alkanesulfonyl chloride or bromide, or C 1 -C 4 alkanesulfonic anhydride, optionally in the presence of an acid acceptor, or b) a compound of Formula C with a compound of formula R ^d CH 2 -HET - wherein one of R ^c and R ^d is -NHR ¹ and the other is a leaving group, and R ¹ and Sev are as defined above reacting, if desired, converting the compound of formula (I) obtained by any of the above processes into a pharmaceutically acceptable acid addition salt thereof. 2. Process according to claim 1, wherein the leaving group is selected from the group consisting of chlorine, bromine or iodine, C 1-4 alkanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy. group. 3. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in the presence of an acid scavenger. 4. A process according to any one of claims 1 to 3, wherein the starting compound of formula (I) wherein R ¹ is -NHSO 2 CH ³ R ¹ is methyl or ethyl, Seven represents a group of formula (1), (2) or (3) in which R ² is hydrogen or methyl, X is oxygen or sulfur, R ^b is attached to position a or b -NHSO2CH3. A process for the preparation of a compound of formula IA according to claim 1, wherein the N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine is reacted with methanesulfonyl chloride. in the presence of an acid binder. A process for the preparation of a compound of formula (IB) according to claim 1, characterized in that: a) reacting N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethylamine with methanesulfonyl chloride in the presence of an acid acceptor; or b) 4- [2- (methylamino) ethyl] methanesulfonanilide is reacted with 2-chloromethyl-6-methanesulfonamidoquinoline. The process according to claim 5 or 6, wherein the acid acceptor is pyridine. A process for the preparation of a pharmaceutical composition comprising mixing as an active ingredient a compound of formula (I) or a salt thereof according to claim 1, wherein R ¹ and Sev are as defined in claim 1, with a pharmaceutically acceptable carrier and / or excipient; for administration to a pharmaceutical composition.