PL158277B1 - Method of obtaining novel sulfonamides - Google Patents

Abstract

1. A method of producing new sulphonamides with the formula presented in 1 and their pharmacologically accepted salts, where 1 R<1> stands for C1-C4 alkyl group and Het stands for a group with the formula presented in 2,3 or 4 where R<2> stands for the hydrogen atom, methyl or ethyl group and X stands for the oxygen or sulphur atom or the group of the formula NR<4>, in which R<4> stands for the hydrogen atom or a methyl group, characterized in that the compound of the formula 1a, where R<a> stands for -NH2 group or -NHSO2(C1-C4 alkyl) group, R<1> has the meaning specified above and Het stands for the group of the formula 2a, 3a or 4a, and in these formulae R<2> and X have the meaning specified above and R<b> stands for -NH2 group or -NHSO2(C1-C4 alkyl) group, provided that both substituents R<a> and R<b> do not stand at the same time for -NHSO2(C1-C4-alkyl) group, is acylated with C1-C4 alkane sulfonyl chloride or C1-C4 alkane sulfonyl bromide or with C1-C4 alkane sulfonyl anhydride and the obtained product with the formula presented in 1 is possibly transformed into a pharmacologically accepted salt.<IMAGE>

Description

The present invention relates to a process for the preparation of novel anti-arrhythmia sulfonamides.

The compounds of the present invention prolong the duration of the potential action in the myocardium and in the vascular tissue and thereby increase resistance to premature stimuli. These compounds therefore belong to class III of anti-arrhythmic agents according to the Vaughan Williams classification (Anti-Arrhythmic Action, E. M. Vaughan Williamś, Academic Press, 1980). They are effective in atria, ventricles, and conducting tissue, both in vitro and in vivo, and are therefore useful in the prevention and treatment of a wide variety of ventricular and extraventricular arrhythmias, including atrial fibrillation and ventricular fibrillation. The compounds in question do not alter the speed of impulse conduction and therefore tend to be less likely than currently used drugs, mainly class I, to induce or exacerbate arrhythmias, as well as having fewer neurological side effects. Some of the compounds in question also have some positive inotropic activity and, as a result of this feature, are particularly advantageous for patients with impaired blood pumping function.

The compounds of formula 1 as well as their salts are prepared by the process of the invention, in which formula 1 R ¹ represents a C 1 -C 4 alkyl group and Het represents a group of formula 2, 3 or 4, in which

R ² represents a hydrogen atom, a methyl or ethyl group and X represents an oxygen or sulfur atom or a group of the formula NR ⁴ , wherein R ⁴ is a hydrogen atom or a methyl group.

The starting materials for the preparation of compounds of formula 1 can be compounds of formula Ia in which R ^a is a -NH2 group or a -NHSOa (Ci-C4alkyl) group, R ¹ is as defined above and Het is a group of formula 2a, 3a or 4a in which formulas R ² and X are as defined above and R ^b is -NH 2 or a group -NHSO 2 (C-C4alkiIową) or the compounds of formula Ib, wherein R has the same meaning as R ^a in formula la R is as hereinbefore defined and Het represents a group of formula 2b, 3b or 4b, in which formulas R 2 and X are as defined above, and R ³ is -NH 2 or a group -NHSO 2 (Ci-C4 alkyl). Appearing in formula la R a, R ^b and R 3 can also denote a group -NO 2, easy to transform by reduction in a -NH2 group, wherein if one of the radicals present in the formula means a -NO 2 group, the other is other than the - NH2.

The compounds of formula I show anti-arrhythmia activity. The remaining compounds are synthetic intermediates.

In the compounds of formula 1b, R is preferably -NHSO2CH3, Ri is preferably methyl or ethyl, Het is 2b, 3b or 4b, where R2 is preferably hydrogen or methyl, R3 is preferably -NHSO2CH3, and X is preferably oxygen or sulfur.

R3 is preferably in the 6-position or 7-position if Het is a quinolyl group, and in the 5-position or 5-position in other cases, i.e. when the benzene ring is fused to a 5-membered heterocyclic ring.

The preferred concrete compounds are those of formulas 5 and 6.

Pharmacologically acceptable salts of compounds of Formula I include acid addition salts formed with acids which form non-toxic acid addition salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, benzenesulfonate and p-toluenesulfonate. These salts are prepared by known methods.

The process according to the invention for the preparation of sulfonamides of formula II and their salts, in which formula Ri and Het are as defined above, consists in that the compound of formula Ia in which Ra is -NH2 or -NHSO2 (Ci-C4alkyl), Ri It is as defined above and Het is a group of formula 2a, 3a or 4a, in which formulas R ² and X are as defined above and Rb is -NH2 or a group NHSO2 (Ci-C ^ alkyl group), provided that both Ra and Rb are not simultaneously -NHSO2 (C1-C4alkyl) group, are acylated with C1-C4 alkanesulfonyl chloride or bromide or C1-C4 alkanesulfonic anhydride and optionally the resulting product of the formula and converted into a pharmacologically acceptable salt. If R and R ³ are both -NH 2, then of course at least two equivalents of the acylating agent will be needed, and naturally both groups in the final product will be the same.

The reaction is usually 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 advantageous when an alkanesulfonyl chloride or bromide is used. In fact, it is particularly convenient to carry out the reaction with the alkanesulfonyl chloride in pyridine. The product of formula I can then be isolated and purified by known methods.

The starting materials for the acylation reactions are prepared by known methods, for example as shown in the scheme and the figure. The compound of formula 7 is reacted with a compound of formula Q-CH2-Het in which formulas R and Het are as defined above for formula Ib, and Q is a leaving group such as chlorine, bromine, iodine or a methanesulfonyloxy group. the reaction is carried out in the presence of K2CO3 in an organic solvent under reflux conditions. The resulting compound of formula 8 is subjected to catalytic hydrogenation, e.g. with hydrogen against Raney nickel, at a pressure of 344 kPa to give the product of formula 9.

Another method shown in Scheme 2 of the figure is to react a compound of formula I with a compound of formula RHN-CH2-Het, wherein R, Het, and Q have the same meanings as described above for formula 7 and formula Q-CH2 -Het, under the same conditions as in

In the first step of the process described in Scheme 1. The obtained product of formula 8 is subjected to catalytic hydrogenation under the conditions described above. The hydrogenation reaction gives the compound of formula 9.

The methods shown in Schemes 1 and 2 can also be carried out with starting materials in which R ³ in the group Het is nitro instead of C1 -C4 alkanesulphonamido, which affords an intermediate compound dwunitrowy, which can be reduced by catalytic hydrogenation to the diamino compound from the starting material of formula Ib in which R and R3 are both amino.

The last method shown in Scheme 3 of the figure is to react a compound of formula 11 with a compound of formula Q-CH2-Het where R3 in the Het group is nitro under reflux in an organic solvent and subjecting the resulting compound to of the formula 12, in which R3 in the Het group is as defined above, catalytic hydrogenation, e.g. with hydrogen against Raneya nickel at a pressure of 344 kPa. In formulas 1112 and 13 of scheme, R is C1-C4 alkyl, Het is a nitro-substituted heterocycle of formula 2b, 3b or 4b, and Q is a leaving group as shown in scheme 1.

The starting materials used in the above-discussed processes are either known compounds or can be obtained by known methods, e.g. as described in the section of the Examples relating to the preparation of starting materials.

In order to evaluate the effects of the novel compounds on the vestibular immunity, the right half of the guinea pigs are placed in a bath containing saline solution and one end is connected to the power transducer. Tissues are stimulated at 1 Hz using field electrodes. The Effective Duration of Immunity (ERP) is measured by applying the premature stimulus S2 after each 8th Si baseline stimulus. The coupled interval S1S2 is gradually increased until Si repeatedly reveals a reaction transfer. It is known as ERP. The concentration of compound necessary to increase the ERP by 25% (ED25) is thus determined. ERP is also measured on the guinea pig's right papillary muscles incubated in saline. Muscles are stimulated at one end with bipolar electrodes and the obtained electrograph is recorded at the opposite end by a unipolar electrode surface, ERP is determined as above using the additional stimulus technique. Conduction time is obtained from a digital oscilloscope by measuring the time interval between the stimulus artefect and the peak of the electrograph, that is, the time required for the pulse to travel through the length of the muscle.

Atrial and ventricular ERP are also measured in anaesthetized or not asleep dogs by using the supplemental stimulus technique when measuring atrial or right ventricular stimulus at a constant rate.

The compounds of Formula 1 may be administered alone, but are typically used in admixture with a pharmaceutical carrier depending on the intended route of administration and standard pharmaceutical practice. They can be used both for patients suffering from arrhythmia and prophylactically in people suspected of developing arrhythmia. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring additives. They can also be administered by the parenteral route, for example, intravenously, intramuscularly, or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other solutes, for example an amount of salt or glucose which makes the solution isotonic with blood.

For human administration for therapeutic or prophylactic purposes, such as ventricular or extraventricular arrhythmias, including atrial and ventricular fibrillation, oral doses of compounds of formula I in the range of 2 to 150 mg per day, taken in maximum 4 servings a day for an average adult patient (70 kg). For intravenous administration, the expected single dose will be in the range 1.0 to 20 mg. Severe cases of cardiac arrhythmia are preferably treated by intravenous administration of the drug to rapidly restore normal heart rhythm. So for the average adult

Individual tablets or capsules may contain 2-50 mg of the active compound in a suitable pharmaceutically acceptable carrier or vehicle. Deviations from these ranges may occur depending on the weight and condition of the patient being treated, and will be known to those of skill in the art.

Thus, a pharmaceutical composition comprises a compound of Formula 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient or carrier, and ingestion of such composition will counteract or reduce arrhythmia in humans.

The following examples illustrate the process according to the invention, Examples 1-7 illustrate the preparation of the compounds of formula 1 and Examples VIII-XVII illustrate the preparation of new starting compounds.

Example 1 N-Methylo-N- (3-methyl-5-methanesulfonamidobenzafuryl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 4).

Chloride was added dropwise to a solution of N-Methyl-N- (3-methyl-5-aminobenzofuryl-2-methyl) -4-methanesulfonamidophenethylamine (prepared in Example XVB, 0.78 g, 1.68 mmol) in pyridine (7 ml). methanesulfonyl (0.21 g, 1.85 mmol) and the solution was then stirred 60 hours at room temperature. The solvent was evaporated and the residue was triturated with toluene. The toluene was decanted, the residue was measured with aqueous sodium bicarbonate solution and the precipitate was collected by filtration and recrystallized from methanol to give the title compound, 0.38 g, mp 142-143.5 ° C.

Analysis (%) for C21H27N3O5S2:

Found: C 54.4 H 5.8 N 9.1

Calculated: C 54.2 H 5.85 N 9.0

Example II. N-Methyl-N- (5-methanesulfonamidobenzofuryl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 5).

To a solution of N-Methyl-N- (5-aminobenzofuryl-2-methyl) -4-aminophenethylamine (prepared for example X, 0.9 g, 3.0 mmol) in pyridine (25 ml) was added dropwise methanesulfonyl chloride (0, 76 g, 6.6 mmol) and stirred for 18 hours at room temperature. The solvent was then evaporated and the residue was diluted with an aqueous sodium hydrogen carbonate solution and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated and the residue was chromatographed on silica gel eluted with ethyl acetate. Product containing fractions were combined and evaporated and the resulting solid was recrystallized from ethyl acetate / methanol to afford the title compound, 0.35 g, mp 177-179 ° C.

Analysis (%) for C20H25N3O5S2:

Found: C 53.2 H 5.7 N 9.0

Calculated: C 53.2 H 5 Fi N 9.3

Example III. N-Methyl-N- (5-methanesulfonamidobenzoxazolyl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 6).

Treatment of methanesulfonyl chloride (0.38 g, 3.3 mmol) and N-methyl-N- (5-aminobenzoxazolyl-2-methyl) -4-aminophenethylamine (prepared in Example 7IC, 0.45 g, 1.5 mmol) in pyridine (20 ml) reactions under conditions similar to those described in Example 2 gave the title compound (from ethanol), 0.25 g, m.p. 174-176 ° C.

Analysis (%) for C19H24N4O5S2:

Found: C 50.4 H 5.1 N 12.4

Calculated: C 50.4 H 5.35 N 12.4

Example IV. N-Methyl-N- (6-methanesulfonamidobenzofuryl-2-methyl) -4-methanesulfonylamidophenethylamine (scheme 7).

Treatment of methanesulfonyl chloride (0.21 g, 1.8 mmol) and N-methyl-N- (6-aminobenzofuryl-2-methyl) -4-aminophenethylamine (prepared in Example 9, 0.24 g, 0.82 mmol) in pyridine (3 mL) reaction under conditions similar to those described in Example 2 gave the title compound as an oil, 0.18g.

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Analysis (%) for C20H25N3O5S2:

Found: C 53.0 H 5.7 N 9.1

Calculated: C 53.2 H 5.6 N 9.3

Example 5 N-Methyl-N- (6-methanesulfonamidoquinolyl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 8).

Treatment of methanesulfonyl chloride (0.15 g, 1.3 mmol) and N-methyl-N- (6-aminoquinolyl-2-methyl) -4-aminophenethylamine (prepared in Example 11, 0.17 g, 0.37 mmol) in pyridine (20 mL) reaction under conditions similar to those described in Example 2 gave the title compound, 0.70 g (from ethyl acetate), mp 163-165 ° C.

Analysis (%) for C21H26N4O4S:

Found: C 54.3 H 5.45 N 12.1

Calculated: C 54.3 H 577 N 12.1

Example VI. N-Methyl-N- (5-methanesulfonamido-2-benzo [b] thienylmethyl) -4-methanesulfonamidophenethylamine (scheme 9).

Treatment of N-methyl-N- (5-amino-2-benzo [b] thienylmethyl) -4-aminophenethylamine) (prepared in Example XVII, 0.26 g) with methanesulfonyl chloride (0.23 g) in pyridine by the method of Example 2 gave the title compound, 0.167g, mp 175-177 ° C.

Analysis (%) for C20H25N3O4S3:

Found: C 50.99 H 5.39 N 8.93

Calculated: C 51.37 H 5.39 N 8.99

Example VII. N-Ethyl-N- (6-methanesulfonamidoquinolyl-2-methyl) -4-methanesulfonamidophenethylamine hydrochloride (Scheme 10).

Methanesulfonyl chloride (0.1 g, 1.29 mmol) was reacted with N-methyl-N- (6-aminoquinolyl-2-methyl) -4-methanesulfonamidophenethylamine (Example XVIB, 0.51 g, 1.23 mmol) in pyridine similarly as in Example II to give the free base of the title compound as gum. This gum was dissolved in ethyl acetate and the solution was diluted with ethereal hydrogen chloride and evaporated to dryness. The residue was triturated with ether to give the title compound as a foam, 0.06 g, m.p. 96 ° C.

Analysis (%) for C22H28N4O4S2HC1H2O:

Found: C 50.2 H 5.5 N 10.0

Calculated: C 49.75 H 5.9 N 10.5.

Example VIII.

(A) 2-chloromethyl-5-nitrobenzoxazole (scheme 11).

2-Amino-4-nitrophenol (10 g, 65 mmol) and ethyl chloroacetate imide hydrochloride (15.4 g, 97.5 mmol) were heated for 18 hours under reflux in ethanol (100 ml). The solvent was then removed by evaporation in vacuo and the residue recrystallized from ethanol to give the title compound, 9.0 g, mp 216-217 ° C.

Analysis (%) for C8H5CIN2O3:

Found: C 43.15 H 2.3 N 13.25

Calculated: C 45.2 H 2.4 N 13.2 (B) N-Mttyl-N- (5-nitrobtzoxalylmethyl) -4-nitrophthylamine (scheme 12).

2-Cl-1-methyl-5-nitrobenzoxazole (2.85 g, 13.4 mmol), N-methyl-1-nitrophenethylamine (J.

OC [1956], 21.45 (2.2 g, 12.2 mmol), potassium carbonate (1.85 g, 13.4 mmol) and sodium iodide (2.0 g, 13.4 mmol) were heated for 3 days at reflux in acetonitrile (50 ml). Then the solvent was evaporated, the residue was diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO 4),

158 277 was filtered and evaporated to dryness. The resulting oil was diluted with ether and the clear liquid was decanted and evaporated to dryness to give an orange solid which was recrystallized from isopropanol to give the title compound 0.80g.

¹ H NMR (CDCl): <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-Metrlo-N- (5-aminobenzoxazolyl-2-methyl) -4-aminophenethylamine (scheme 13).

N-Methyl-N- (5-nitrobenzoxazolyl-2-methyl) -4-nitrophenethylamine (0.78 g, 2.2 mmol) in ethanol (50 mL) containing Raney nickel (0.1 g) was stirred under an atmosphere of hydrogen ( 344.7 kPa) for 18 hours, after which time thin-layer chromatography has shown that all starting materials have been consumed [silica chromatography plates, developed with methylene chloride / methanol (19: 1) as eluent]. The reaction mixture was then filtered and evaporated to give an oil which was azeotroped with toluene and triturated with ether. The ether was decanted and evaporated to give the title compound as an oil which was used directly without further purification: 0.45g.

Examples ΙΧ-ΧΙ. The compounds of Examples 9 and 10 were prepared similarly to Example 8 (C) by reduction of the corresponding dinitro compounds (see Examples 13 and 12) using hydrogen, Raney nickel, ethanol, a pressure of 344.7 kPa and room temperature and reaction times of 4 and 17, respectively. hours. The compound of Example 11 was prepared similarly to Example VIII (C), but using hydrogen, palladium on carbon in ethanol and a pressure of 206.8 kPa for 3 hours, the starting two liter compound being prepared in Example 14. The reaction is illustrated in Scheme 14 in the figure, while the table lists the substituents present in the formulas of the starting and produced compounds, and the results of the spectral analysis.

Table

Example No. -Hci'-NOz -Het'-NH ₂ ¹ H-NMR IX pattern 14 pattern 15 β (CDCb). 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) X pattern 16 pattern 17 <(DMSO / TFA): 7.75 (d, 2H), 7.3 (m, 5H), 4.7 (d, 2H), 3.4 (q, 4H), 2.85 (s, 3H) XI pattern 18 pattern 19 -

Example XII.

(A) 4- (isopropylideneaminoxy) nitrobenzene (scheme 15).

A solution of propanone oxime (30 g, 0.4 mol) in dry tetrahydrofuran (300 ml) was added slowly to a slurry of sodium hydride (10.8 g, 0.45 mol) in dry tetrahydrofuran (50 ml). After gas evolution ceased, dimethylsulfoxide (100 ml) and 4-fluoronitrobenzene (57.85 g, 0.41 mol) were added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was then poured into water and extracted three times with ether. The combined ether extracts were washed with water, dried (MgSO 4) and evaporated to give the title compound which was crystallized in hexane and filtered to give 64 g. A sample (7 g) was recrystallized from ethanol to give 5 g, mp 104-106 ° C.

Analysis (%) for C9H10N2O3:

Found: C 55.6 H 5.05 N 14.35

Calculated: C 55.7 H 5.2 N 14.4 (B) 2-Methyl-5-nithiobenzofuran (scheme 16).

To glacial acetic acid (530 ml) containing hydrogen chloride gas (25 g) was added 4- (isoproprlideneaminoxr) nitrobenzene (60 g, 0.309 mol) and heated for 18 hours at 100 ° C. The solvent was evaporated and the residue was azeotroped with cyclohexane to give an oil which 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, dried (MgSO 4) and evaporated to give the title compound, 46 g. A sample (5 g) recrystallized from isopropanol to give 2.5 g of a compound, mp 93-95 ° C. C.

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Analysis (%) for C9H7NO3:

Found: C 61.2 H 4 J N 7.9

Calculated: C 61.0 H 4.0 N 7.9 (C) 2-Bromomethyl-5-nitrobenzofuran (scheme 17).

N-Bromosuccinimide (1.1 g, 6.2 mol) was added portionwise to a solution of 2-methyl-5-nitrobenzofuran (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg) in carbon tetrachloride (50 ml ) and the reaction mixture was heated to reflux for 6 hours in the presence of bright light. The reaction mixture was then cooled, filtered and the filtrate evaporated to dryness. The residue was recrystallized from petroleum ether to give the title compound 0.75 g, mp 96-98 ° C.

Analysis (%) for CgHeBrNCb:

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-nitrobenzofuryl-2-methyl) -4-nitrophenethylamine (scheme 18).

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

¹ H NMR (DMSO / TFA): δ 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 (s, 3H).

Example XIII.

(λ) 2-Bromomethyl-6-nitrobenzofuran (scheme 19).

N-Bromosuccinimide ("NBS" in scheme 19) (1.1 Ig, 6.2 mmol) was added to a solution of 2-methyl-6-niirobenzofuran (1.00 g, 5.65 mmol) and azobisisobutyronitrile (20 mg) in carbon tetrachloride and the mixture was heated to reflux for one and a half hours in the presence of bright light. The solvent was then evaporated and the residue dissolved in methylene chloride, washed with water, dried (MgSO 4), evaporated to dryness, and purified by silica gel column chromatography eluting with methylene chloride / hexane (7: 3). Product containing fractions were combined and evaporated to afford the title compound 1.43 g.

1H NMR clearly shows that the product contained 20% 2-dibromomethyl-6-nitrobenzofuran, however it was not considered necessary to remove this compound and the product was used directly without further purification.

(B) N-Methyl-N- (6-nitrobenzoxazolyl-2-methyl) -4-nitrophenethylamine (scheme 20).

N-Methyl-4-nitrophenethylamine (0.84 g, 4.7 mmol), 2-bromomethyl-6-nitrobenzofuran (1.2 g, 4.7 mmol), sodium iodide (0.7 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) was refluxed in acetonitrile for 18 hours. The cooled reaction mixture was then filtered and the filtrate evaporated to dryness and purified by chromatography on silica gel eluting with methylene chloride / hexane (1: 1) and then with methylene chloride / methanol (19: 1). The product-containing fractions were combined and evaporated, and the residue was treated with ethanol decolorizing charcoal to give an oil which solidified on standing. Recrystallization of the solid from ethanol / methylene chloride gave the title compound, 0.27 g, mp 69-69.5 ° C.

Analysis (%) for C18H17N3O5:

Found: C 60.8 H 4.8 N 118

Calculated: C 60.8 H 4.8 N 118

1 H NMR (CDCl 3): 6 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), 2.95 (t, 3H), 2.75 (t, 3H), 2.4 (s, 3H).

158 277 9

Example XIV. N-Methyl-N- (6-nitroquinolyl-2-methyl) -4-nitrophenethylamine (scheme 21).

N-Methyl-4-nitrophenethylamine (0.39 g, 2.15 mmol) and 2-chloromethyl-6-nitroquinoline (0.40 g, 2.1 mmol) were refluxed for 6 hours in ethanol (30 ml). Then the solvent was evaporated and the residue was diluted with 2M hydrochloric acid solution and extracted with methylene chloride. The aqueous layer was basified with aq. Sodium carbonate (to pH ~ 12) and extracted three times with methylene chloride. The latter organic extracts were combined, dried (MgSO 4) and evaporated to give an oil which was purified by column chromatography on silica gel that was eluted with methylene chloride containing methanol (0% to 1%). The fractions containing the product were combined and evaporated to give a solid which crystallized from ethanol to give the title compound 0.21 g, mp 104-105 ° C.

Analysis (%) for C19H18N4O4:

Found: C 62.4 H 4 ^ 77 N 15.2

Calculated: C 62.7 H 4.97 N 15.3.

¹ HNMR (CDCl3): <5 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), 2.8 (t, 2H), 2.4 (s, 3H).

Example XV.

(A) N-Methyl-N- (3-methyl-5-niirobenzofuryl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 22).

N-Methyl-4-methanosIphonamidophenethylammonium (1.66 g, 7.3 mmol) and 2-chloromethyl-3-methyl-5-nitrobenzofuran (0.82 g, 3.2 mmol) were heated for 3 hours under reflux in ethanol ( 20 ml). The solvent was then evaporated and the residue was purified by column chromatography on silica gel eluting with methylene chloride / hexane (4: 1) then with methylene chloride containing methanol (0% to 5%). The fractions containing the product were combined and evaporated and the residue recrystallized from ethanol to give the title compound, 1.52 g, mp 124-124.5 ° C.

Analysis (%) for C20H23N3O3S:

Found: C 57/7 H 5.65 N 10.0

Calculated: C 2 * 7.5 H 5.55 N 10.1

1H NMR (CDCls): δ 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-aminobenzofuryl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 23).

Catalytic hydrogenation of the product from Part (A) (0.7 g) similar to Example VIII (C), over a reaction time of 4 hours, gave the title compound (0.65 g).

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 XVI.

(A) N-Ethyl-N- (6-nitroquinolyl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 24).

N-Ethyl-4-methanesulfonamidophenethylamine (1.7 g, 7.0 mmol) and 2-chloromethyl-6-nitroquinoline (0.78 g, 4.1 mmol) were refluxed for 4 hours in ethanol (50 ml). The solvent was then evaporated and the residue was diluted with an aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layer was dried (MgSO4), evaporated and the residue was purified by column chromatography on silica gel eluting with methylene chloride. The fractions containing the product were combined and evaporated to give the title compound as an oil, 0.56g.

¹ H NMR (CDCl?): <8.6 (d, 1H), 8,3-8,0 (m, 2H), 7.6 (d, 1H), 7.1 (s, 1H), 7, 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-aminoquinolyl-2-methyl) -4-methanesulfonamidophenethylamine (scheme 25).

158 277

The product of part (A) (0.55 g) was catalytically hydrogenated similar to Example VIII (C) but using hydrogen over 5% palald on carbon in ethyl acetate at 103.4 kPa for 4 hours to give the title compound (0.51 g).

1H NMR (CDCla): δ 7.7 (d, 1H), 7.5 (d, 1H), 7.15 (d, 1H), 6.9 (broad s, 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 XVII.

(A) 2-Chloromethyl-5-nitrobenzo [b] thiophene (scheme 26).

To a mixture of 5-nitrobenzo [b] thiophene-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml) was added dropwise with stirring thionyl chloride (1.0 ml). The solution was stirred 4 hours at room temperature then washed with water followed by aqueous sodium bicarbonate and dried (NazSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave a solid which was crystallized from ethyl acetate to give the title compound, 0.73 g, mp 110-112 ° C, used directly in the next step.

(B) N-Methyl-N- (5-nitro-2-benzo [b] thienylmethyl) -4-nitrophenethylamine (scheme 27).

A mixture of the product from part (A) (3.20 g), N-methyl-4-nitrophenethylamine (2.52 g), anhydrous potassium carbonate (4.0 g) and acetonitrile (40 ml) was heated to reflux. for 20 hours with stirring, then cooled and filtered. The residue was washed with acetonitrile and the combined filtrate and washings were evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane gave first impurities and then pure product. Product containing fractions were evaporated to give the title compound, 4.17 g, mp 76-78 ° C (isopropanol).

Analysis (%) for C18H17N3O4S:

Found: C 57.8 H 4.4 N 111

Calculated: C 58.2 H 4.6 N 113 (C) N-Methyl-N- (5-amino-2-benzo [b] thienylmethyl) -4-aminophenethylamine (scheme 28).

A mixture of the product from part (B) (1.0 g) and stannous chloride dihydrate (6.07 g) in ethanol (100 ml) was heated under reflux for 8 hours and then evaporated. A 20% excess of aqueous sodium hydroxide solution was added and the mixture was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried (NazSO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane / methanol (99: 1) gave impurities followed by further elution with dichloromethane / methanol (98: 2) gave, after collecting and evaporating the appropriate fractions, an oil product (0.30g) which was used directly in the procedure of Example 6.

Scheme 2Θ

158 277

Scheme 20

CHa

0, Ν

Scheme 17

"N ^CH 2 -Het'-NO ₂

N ^{3 NH 2} ^ Cy (CH ₂ ) ₂ - N -CHj Hef NHj

Scheme 14

Scheme 10

158 277

158 277

Formula 16

Pattern 15 _N U

(C, -C ₄ alkyl) SO ₂ NH - V ((H _{2) 2} NHR ₂ + Q CH Het ⁽³ whet R = NO ₂₎

Formula 11 (Cf-aalk O ^ NH

Formula 12

I ₉ (O ^ -NC ^ -Het (R3 = NO2) (ς- icsDsOjNH (O ^ -N-ity-Het (r3 = nhJ

Formula 13

Scheme 3

ΝΟζΟ ^ οΗΟ ^ - Q + RNH- C ^ -Het Formula 10

R

HOj '(CH ₂ > _ H - CH ₂ Het

Formula 8

Formula 9

Scheme 2

HHR ♦ Q - ^ 2 ~ ^H et

Formula 7

R

HO ₂ - (C- ² ) ₂ H CH ₂ - Het

Pattern 8

NH.

R

And (C 1 -N -C 2 -Het

R ^b

Pattern 3 o

Formula 4 a

R ^b

R '

Formula 1a

158 277 / ~ λ? ’

YiCHjk - Ń - CH ₂ -Het

The NHS

Formula 5 ch ₃ εΗ, ϋΟ, ΝΗ ^ / ^^ - Ń-CHjA _n

NHSO2CH3

Formula 6

R ¹ (CfC ₄ alkyl) SO ₂ NH ^^> - (^ C ^ H ₂ ) ₂ -N- ^ CH ₂ -Het

Formula 1 [30 | - MHSO ^ (C ^ -C ₄ a »<il)

Pattern 2

Pattern Z

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Claims (6)

Patent claims 1. A process for preparing sulfonamides of formula 1 and pharmaceutically acceptable salts thereof, wherein one R1 is -C Cąalkilową and Het represents a group of Formula 2,3 or 4, in which formulas R ² represents hydrogen, methyl or ethyl, and X represents an oxygen or sulfur atom or a radical of the formula NR4 in which R4 is hydrogen or methyl, characterized in that a compound of formula Ia wherein R ^a is -NH 2 or a -NHSC> 2 (Ci-C4alkiiową), ^R1 is as defined above and Het is a group of formula 2a, 3a or 4a, in which formulas R (X and are as defined above and R ^b is a group -NH (or a -NHSC ^ -C Caaakilową), provided that both substituents R a and R ^b do not simultaneously represent a group -NHSO ((Ci-C4alkyl) is acylated with an acid chloride or bromide or Ci-C4alkanosulfonylowym -C C4alkanosulfonowym anhydride and, optionally, the obtained product of formula 1 is converted into a pharmacologically acceptable salt. 2. The method according to p. The process of claim 1, wherein the reaction is carried out in the presence of an acid acceptor. 3. The method according to p. 2. The process of claim 1, characterized in that for the preparation of the compound of formula 1b in which R is -NHSO (CH3, R1 is methyl or ethyl and Het is a group of formula 2b, 3b or 4b, in which R (represents atom hydrogen or methyl, X is oxygen or sulfur, and R ^3, attached in the a or b groups Het represents a group -NHSO (CH3 acylating a compound of formula Ib, wherein R is a group -NH (or - NHSO (CH3, Het represents a group of formula 2b, 3b or 4b, in which formulas R (X and are as defined above and R ³ is a group -NH (or a group -NHSO (CH3, with the proviso that both substituents R and R ³ are not simultaneously a -NHSC2CH3 group. 4. The method according to p. The process of claim 1, wherein N-methyl-N- (5-aminobenzofuryl-2-methyl) -4-aminophenethylamine is reacted with methanesulfonyl chloride in the presence of an acid acceptor for the preparation of the compound of formula 5. 5. The method according to p. The process of claim 1, wherein N-methyl-N- (6-aminoquinolyl-2-methyl) -4-aminophenethylamine is reacted with methanesulfonyl chloride in the presence of an acid acceptor for the preparation of the compound of formula 6. 6. The method according to p. The process as claimed in claim 4 or 5, characterized in that pyridine is used as the acid acceptor.