PT86702B - PROCESS FOR PREPAPPING METHANE-SULFONAMIDE-REPLACED PHENETHYLAMINES - 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

PROCESS FOR THE PREPARATION OF SUBSTITUTED METHAN-SULPHONAMIDE-PHENETYLAMINS and their salts, where R is

-N0 ₂ ; R4 is C1 -C4 alkyl; and

-NHS0 ₂ (C ^C Calkyl), -NHg or ”Het is a group of the formula: -

or C _O H _K ; It ^{2 5} 4

S or NR, which, when one of R and R ^J is -NOg 'ch ₃ and X is 0,

-NHSO ₂ (σ _χ -0 _Ε alkyl) where R ^ is H or CH ^;

z -Km then the

V ’with another

The compounds of formula (a), in which both R and R ^J are -NHSOg (0 _χ -0 ^ alkyl) are antiarrhythmic agents. The remaining compounds of formula (à) are syntactic intermediates.

The process of preparing these compounds consists, for example, of reacting an analog of (à) in which R and -NHg or -NHSOg (C ^ -C ^ alkyl) and in which, in the Het group, R ^ and -NHg or -NHSOg (C ^ -C ^ alkyl), with the proviso that R and R ^ are not both -NHSOg (C ^ -C ^ alkyl), with a C ^ -C ^ -sulfonyl alkane chloride or bromide or with a C ^-C ^-sulfonic alkane anhydride.

This invention concerns certain sulfonamides, which are antiarrhythmic agents, and intermediates for that purpose.

The compounds of the invention prolong the duration of the action potential in the cardiac muscle and in the conductive tissue, and, consequently, increase the refractivity to premature stimuli. And therefore, they are Class III antiarrhythmic agents, according to the classification of Vaughan Williams (Anti-Arrhythmic Action, E.M. Vaughan Ifilliams, Academic Press, 1980). They are effective in the atria, ventricles and conductive tissues, both in vitro and in vivo, and are therefore useful in preventing and treating a wide variety of ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation. Since they do not change the speed at which impulses are conducted, they are less likely, than current drugs (most of Class I), to precipitate or aggravate arrhythmias, and also produce fewer neurological side effects. . Some of the compounds also have some positive inotropic activity and, therefore, are particularly beneficial in patients with impaired cardiac pumping function.

And so, the invention establishes compounds of the formula

(A) and its salts, where R is -N0 ₂ , -NH ₂ or '-NHSC> ₂ (C 1 -C 4 alkyl);

# ** **

R is alkyl of

4 © ”Het” is a group of the formula: -

where R ² is H, CH ^ or kil C ^ -C ^); and X is 0, with the proviso that another is not -NHg.

° 2 ^H 5 ^{! R} 4 - ^N0 2 '- ™ 2

S or NR where R is when one of R and R or -NHSOg (alH or CH ^;

is ~ Νθ2 ' ^err k o o

The compounds of formula (a), in which R and R3 are -NHSOg (alkyl have activity as antiarrhythmic agents. The remaining compounds are intermediates for synthesis.

And so, the invention also establishes antiarrhythmic agents of the formula $ 1

R "

and their pharmaceutically acceptable salts, where R is -NHSO ^ (C 1-4 alkyl);

R4 is C1 -C4 alkyl;

and Ilot is a group of the formula: --- (I)

on what

X is 0,

R ² is H, CH 3 S or NR 2 in or C _O H _K ; R ⁹ is ² 4 ⁵ , that R and II or

-NHS0 (C1 -C4 alkyl); and ch.

^{or C} 2 ^H 5 'is preferably -NHSO ^ CH ^ and

In compounds (l), R © preferably NHSOgCI ^, R ¹ is preferably CII „or 0 _Λ Η„, R ² is preferably H or CII ^, R ⁹ X is preferably 0 or S.

_The substituent R ^ is preferably in position 6 or 7, when Ilet ”contains a quinolyl group, in position 5 or 6 in other cases (that is, when the benzene ring is condensed with a 5-membered heterocycle).

Preferred individual compounds have the formulas

NHSO ₂ CH ₃

(IB).

The pharmaceutically acceptable salts of the compounds of formula (i) include the acid addition salts formed with acids that form acid addition salts formed with acids that form non-toxic acid addition salts, containing pharmaceutically acceptable anions, such as hydrochloride salts , hydrobromide, iodhydrate sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate '♦ The salts are prepared by conventional techniques.

For the assessment of the effects of compounds on atrial refractivity, right guinea pigs are installed in a bath containing a physiological saline solution, and one end is connected to a force transducer. The tissues are stimulated at 1 Hz, using field electrodes. The effective refractory period (ERP) is measured by the introduction of premature stimuli (Sg) after each eighth basic stimulus (S ^). The coupling interval S ^ Sg is gradually increased until Sg gives rise reproductively to a prolonged reaction. This is defined as the ERP. The concentration of the compound, required to increase ERP by 25% (EDg ^), is then determined.

ERP is also measured in the right papillary muscles of the guinea pig, incubated in physiological saline solution ^ The muscles are stimulated at one end, using bipolar electrodes, and the propagated electrogram is recorded at the opposite end, using an electrode unipolar surface. ERP is determined as in the previous one, using the technique of extra-stimulus. The conduction time is obtained from a digital accumulation oscilloscope, measuring

Atrial and ventricular ERP are the interval between the stimulus artifact and the peak of the electrogram (that is, the time required for the impulse to travel along the length of the muscle).

also, measured in anesthetized or conscious dogs, by the technique of extra-stimuli, while the atrium or right ventricle is being measured at a constant pace.

The compounds of formula (i) can be administered alone, but are generally administered in admixture with a pharmaceutical carrier, selected in view of the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmias, and prophylactically, to those who are likely to develop arrhythmias. For example, they can be administered orally, in the form of tablets, containing excipients such as lactose starch, or in capsules, either alone or in admixture with excipients, or in the form of elixirs or suspensions, containing flavoring agents. or dyes. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution, which may contain other solutes, for example, sufficient salts or glucose, to make the solution isotonic.

For administration to a man, in the curative or prophylactic treatment of heart diseases such as ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation, it is assumed that the oral doses of the compounds of formula (i) are in the range of 2 to 150 mg per day, taken in and up to 4 divided doses per day, for an average adult patient (70 kg). Doses for intravenous administration are assumed to be in the range of 1.0 to 20 mg, per single dose, as required. A severe cardiac arrhythmia is preferably treated by the intravenous route, in order to effect a rapid transformation in the normal rhythm. Thus, for a typical adult patient, individual tablets or capsules can

contain from 2 to 50 mg of the active compound, in a suitable pharmaceutically acceptable carrier or carrier. Variations can arise, depending on the weight or disease of the patient to be treated, as is known to medical experts.

Thus, the invention under consideration establishes a pharmaceutical composition, consisting of a compound of formula (i), as established above, or a pharmaceutically acceptable salt thereof, | together with a pharmaceutically acceptable diluent or carrier.

The invention also establishes a process to prevent, or to reduce cardiac arrhythmias, in the human being, which is constituted by the administration to said human being, of an efficient amount of a compound of the formula (l), or of its salt pharmaceutically acceptable, or a pharmaceutical composition as set out in the foregoing.

The invention further establishes a compound of the formula (i), or a pharmaceutically acceptable salt thereof, for use as a medicament, particularly for use as an antiarrhythmic agent.

The invention also establishes the use of a compound of the formula (i), or a pharmaceutically acceptable salt thereof, for the production of a medicament, for the prevention, or for the reduction, of cardiac arrhythmias.

The compounds of the formula (i) can be prepared by the following general routes: (1) The first route involves the acylation of a compound of the formula (a), in which R and / or R ^J is -NH ^, employing a C ^-Crom-sulfonyl alkane chloride or bromide or a C ^-C ^-sulfonic alkane anhydride. When R and R ^ are -NH ^, of course, at least two equivalents of the acylating agent will be needed, and, as is evident, R and R, in the final product will be the same.

The reaction is carried out, typically, at room temperature, and optionally in the presence of an acid receptor, such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid receptor is particularly useful when an alkanesulfonyl chloride or bromide is used. In fact, it is particularly convenient to carry out the reaction with an alkanesulfonyl chloride in pyridine. The product of formula (1) can then be isolated and purified by conventional means.

The starting substances for this acylation reaction are conventionally available for example as follows: 10-

^K 2 ^CO 3 ' ^reflux , organic solvent (a)

Q-CH ₀ -Het

4.

catalytic hydrogenation H _? / Raney Ni / 50 çsi = 344 kPa)

R

R and Het ”are what have been established for formula (i), and Q is a leaving group such as chlorine, bromine, iodine or meta-ourulfonyloxy.

(B)

+ RNH-CHg-Het

K ₂ CO ₃ , reflux, organic solvent

Catalytic hydrogenation (e.g. Hg / Raney Ni / 344 kPa)

V

(CHg) ₂ -N-CH ₉ -Het

R, Het and Q. are what was established in (a), in the preceding.

(c) Routes (a) and (b) can also be carried out using starting materials where the substituent R ^ in Het "is nitro, instead of C ^ -C ^ -sulfonamido alkane θχ ”ΘΖ (.» In this way, producing a di-nitro intermediate that can be reduced by catalytic hydrogenation to a di-amino starting material, that is, a starting material of formula (a), where both R, like R ^J are amino.

and (d) (alkyl are NH

Reflux, organic solvent (alkyl dg so NH ^C 1 ~ ^C 4 ²

Catalytic hydrogenation (e.g. Hg / Raney Ni / 50 psi = 344 ’<Pa) (alkyl dq gQ

C ~ c 2

Π ^C 4

R is C ^ -C ^ alkyl, Hei ”in the first phase is a substituted heterocycle, with nitro, as established for formula (à), and Q is a starting group, as was established in (a) in the previous .

The starting materials used in (a) to (d) are either known compounds or can be prepared by conventional techniques, for example, by the techniques set out in the Preparations that follow.

(2) The second route, for compounds (i), can be represented, as follows:

(alkyl of

(D

RNH-CH Compounds (t)

R ^ ^- is C ^ -C ^ alkyl, "Het", is what was established for formula (l), and Q is a leaving group, such as chlorine, bromine, iodine, C ^ -C ^ alkane - sulfonyloxy (preferably methanesulfonyloxy), benzenesulfonyloxy or toluenesulfonyloxy. The reaction is carried out, typically in an organic solvent, up to the reflux temperature. It is preferable to carry out the reaction under reflux. The presence of an acid receptor is optional, but it is most useful when Q and Cl, Br or I. Typical acid receptors are pyridine, triethylamine, potassium carbonate and sodium bicarbonate. The starting materials are, once again, known compounds, or can be obtained conventionally

The following examples, where all temperatures are in degrees Centigrade, make clear the preparation of the compounds of formula (l) EXAMPLE 1

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

Methanesulfonyl chloride (0.21 g, 1.85 mmol) was added dropwise and slowly to a solution of N-methyl-N- (3-methyl-5-aminobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine (see Preparation 10B- 0.78, 1.68 mmol) in pyridine (7 ml), and the solution was then stirred at room temperature for 60 hours, the solvent was evaporated and the residue was ground with toluene. The toluene was decanted, the residue was stirred with aqueous sodium bicarbonate, and the precipitate was collected by filtration and recrystallized from methanol, giving the title compound, with the production of 0.38 g, with the melting point 14-22 to 143 ⁹ , 5

Percentage analysis:

Found: C 54.4; H 5.8; N 9.1;

Calculated: C5.2, 2; H 5.85; N 9.0

EXAMPLE 2

N-Methyl-N- (5-methanesulfonamidobenzofur ^ -ylmethyl] ^ -methanesulfonamidophenethylamine

NH

methanesulfonyl chloride (0.76 g, 6.6 mmol) was added dropwise and slowly to a solution of N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (see Preparation 3 - 0.9 g, 3, 'θ mmole) in pyridine (25 ml) and the mixture was stirred at room temperature for 18 hours. The solvent was then evaporated, and the residue was diluted with aqueous sodium bicarbonate, and was extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated, and the residue was purified by chromatography on silica, eluting with ethyl acetate. The product-containing fractions were combined and evaporated, and the resulting solid was recrystallized from ethyl acetate / methanol, giving the title compound, with a production of 0.35 g and a melting point of 177 ² a 179 ² .

as a percentage:

Found: C 53.2; H 5.7; N 9.0

Calculated: C 53.2; H, 5.6; N 9.3

EXAMPLE 3

N-Methyl-N- (5-methanesulfonamidobenzoxazol-2-ylmethyl) -4 — methanesulfonamidophenethylamine

methanesulfonyl chloride (0.38 St 3.3 mmol) and N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (see Preparation 1 C - 0.4-5 g, 1.5 mmole) in pyridine (20 ml) reacting together, under similar conditions to those of Example 2, gave rise to the title compound, with the production of 0.25 S from and with the melting point of 174 ^ to 1762,

Analysis of C ^ H ^ N ^ O ^ Sg, in percentage:

Found: C 50.4; II 5.1; N 12.4

Calculated: C 50.4; H 5.35; N 12; 4

EXAMPLE 4

N-Me t i1-N- (6-methane and sulfonamidobenzofur-2-1m and t i1) -4-methane and sulfonamidophenethylamine

methanesulfonyl chloride (0.21 g, 1.8 mmol) and N-methyl-N- (o-aminobenzo: fur-2-ylmethyl) -4-aminophenethylamine (see Preparation 2 - 0.24 g, 0.82 mmole) in pyridine (3 ml), reacting together under conditions similar to those of Example 2, gave the title compound, like an oil, with the production of 0.18 g.

as a percentage:

Calculated: C 53.2; H 5.6; N 9.3

Found: C 53.0; H 5.7; N 9.1

EXAMPLE 5

N-Methyl-N- (6-methanesulfonamidoquinol-2-ylmethyl) -4-methanes uIfonamidophenethylamine

methanesulfonyl chloride (0.15 g, 1.3 mmol) and N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethylamine (see Preparation 4 - 0.17 g, 0.37 mmol) in pyridine (20 ml), reacting together, under conditions similar to those of Example 2, gave the title compound, with the production of 0.70 g from ethyl acetate, with a melting point of 163 ⁹ to 165 ⁹ .

Analysis of Cg ^ Hg ^ N ^ O ^ S, in percentage:

Found: C 54.3; H 5.45; N 12.1;

Calculated: C 54.5; H 5.7; N 12.1

EXAMPLE

N-Methyl-N- / 5-methanesulfonamido ~ 2-benzo / b 7 ^ 1θηχlmeti17-4-met t s s ulfonamidofene tilamina

treatment of N-methyl-N- (5 ~ amine-2-benzo / b_7thienylmethyl) -4-aminophenethylamine (o, 26 g - see Preparation 13), with methanesulfonyl chloride (0.23 g) in pyridine, according to the procedure of Example 2, gave the title compound, (0.167 g), with a melting point of 175 ² to 177 ² .

Percentage analysis:

Found: C 50.99; H 5.39; N 8.93;

Calculated: C 51.37; H 5.39; N 8.99

EXAMPLE 7

N-ethyl-N- (o-methanesulfonamidoquinol-2-ylmethyl) hydrochloride -4-methanesulfonamidophenethylamine

methanesulfonyl chloride (0.1 g, 1.29 mmol) was reacted with N-ethyl-N- (6-aminoquino3 -2-ylmethyl) -4-methanesulfonamidophenethylamine (see Preparation 11 B - 0.51 g, 1.23 mmol) in pyridine, similarly to the process of Example 2, giving the free base of the title compound, such as a gum. The 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, giving the title compound, as a foam, with the production of 0.06 g, with the point of 962.

Analysis of ^C 22 ^H 28 ^N 4 ° 4 ^S 2 ' ^{HC: L} * ^H 2 ⁰ ' in percentage:

Verified: C 5θ, 2; H 5.5; N 10.0

Calculated: C 4-9.75; H 5.9; N 10.5

EXAMPLE 8

N- (6-Methanesulfonamido-2-quinolylmethyl) -N-methyl-4-methanesulfonamidophenethylamine

4- / 2- (Methylamino) eti 17 years in 1phonanilide (0.228 g, 1 mmole - see Preparation 14 (b) and 2-chloromethyl-6-methanesulfonamidoquinoline (0.135 g, 0.5 mmole - see Preparation 12 (D)), were heated in an ethanol solution (5 ml), to reflux, for 4 hours The solvent was then evaporated in vacuo, and the residue was dissolved in methylene chloride, washed with water, was dried (MgSO4), filtered and evaporated in vacuo. The resulting gum was purified by column chromatography over silica, eluting with methylene chloride containing methanol (0% to 1%). The product was combined and evaporated in vacuo, giving rise to a foam, which crystallized from ethanol, with the production of the title compound of 0.45 g, with the melting point of 1652 to 1662, confirmed, spectroscopically, as being identical to the product of Example 5.

The following Preparations, in which all temperatures are in degrees Centigrade, reveal the preparation of the new starting materials: Preparation 1 (A) 2-Chloromethi1-5-nitrobenzoxazole

2-Amino-4-nitrophenol (10 g, 65 mmol) and ethyl chloroacetimidate hydrochloride (15.4 g, 97.5 mmol) were heated at reflux temperature in ethanol (100 ml) for 18 hours. The solvent was then removed by evaporation in vacuo. and the residue was crystallized again from ethanol, giving the title compound with a production of 9.0 g and a melting point of 2162 to 217®.

Analysis of CgH ^ ClNgO ^, in percentage:

Found: C 45.15; H 2.3; N 13.25; Calculated: C 45.2; H 2.4; 'N 13.2 (Β) N-Meti1-Ν- (5-nit robenzoxazo 1-2-1 lmet11) -4-nitrophenethi1-

the mine

Cl

NH

2-0 loromethyl-5-nitrobenzoxazole (2.85 g, 13.4 mmol), N-methyl-4-nitrophenethylamine (jOC, i / ~ 195u 7, 21, ^ 5) (2.2 g, 12.2 mmole), potassium carbonate (1.85 g, 13.4 mmole) and sodium iodide (2.0, 13.4 mmole) were heated under reflux in acetonitrile (50 ml) for 3 days. The solvent was then evaporated, and the residue was diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with water, dried, filtered and evaporated to dryness. The resulting oil was diluted with ether, and the supernatant was decanted and evaporated to dryness, giving rise to an orange solid, which was recrystallized from isopropanol, giving the title compound, producing 0.80 g .

’Η-R.m.n. (CDC3): = 8.6 (d, 1H); 8.3 (dd, 1H); 8.1 (d, 2H); 7.6 (d, 1H); 7.35 (d, 2H); 3.95 (s, 211); 2.95 (q, 2H);

2.85 (q, 2H); 2.5 (s, 3H) p.p.m.

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

N-Methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine (0.78 g, 2.2 mmol) in ethanol (50 ml) containing Raney nickel (0.1 g), was stirred under a hydrogen atmosphere (50 psi = 3, 7 kPa) for 18 hours, after which the thin layer chromatographic analysis revealed that all the starting material had been consumed / “silica chromatography plates, using methylene chloride / methane1 (19: 1) as solvent_7. The reaction mixture was then filtered and evaporated, yielding an oil, which was azeotroped with toluene and was triturated with ether. The decanted ether was evaporated to give the title compound as an oil, which was used directly, without any further purification, with the production of 0.4-5 g »

HR.m.n. (CDC1): $ = 7.25 (d, 1H); 6.95 (dd, 3H); 6.65 (dd, 1H); 6.6 (d, 2H); 3.85 (s, 2H);

2.7 (s, 411); 2.4 (s, 3H).

Preparations 2 to 4

The compounds of Preparations 2 and were prepared in a similar manner to that of Preparation (θ), by reducing the corresponding di-nitro compounds (see Preparations 6 and 5), using II ^ / Raney Nickel / / ethanol / 50 psi / room temperature, using reaction times of 4 and 17 hours, respectively. The compound of Preparation 4 was prepared in a similar manner to that of Preparation 1 (C), but using H ^ / Pd / C in ethanol, at 30 p.s.i. , for 3 hours, the relevant di-nitro starting material being the subject of Preparation 8.

p.s.í.s are equivalent to 206.8 kPa, and 50 p.s.i. at 344.7 kPa.

Preparation 5 (a) 4- (lsopropylidenoaminoxy) nitrobenzene

A solution of propanone oxime (30 g _t 0.4 mmol) in dry tetrahydrofuran (300 ml) was added slowly to a suspension of sodium hydride (10.8 g, 0.45 mmol) in tetrahydrofuran. dry hydrofuran (50 ml). After gas development was complete, dimethylsulfoxide (100 ml) and 4-fluoronitrobenzene (57.85 g, 0.41 mole) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water, and was extracted three times with ether. The combined ether extracts were washed with water, dried (MgSO4) and evaporated, yielding the title compound, which was granulated in hexane and filtered, yielding 67 g. A sample (7 g) was recrystallized from ethanol, with the production of 5 g and had a melting point of 104Â ° to 10Â °.

Analysis of Ο ^ Η ^ θΝ ^ Ο ^, in percentage:

Found: C 55.6; II 5.05; N 14.35;

Calculated: C 55.7; H 5.2; N 14.4: -29.

(Β) 2-Meti1-5-nitrobenzofuran

4- (Isopropylideneaminoxy) nitrobenzene (60 g, 0.309 mole) was added to the crystallized acetic acid (530 ml) containing hydrogen chloride gas (25 g), θ the mixture was heated at 1002 ° C for 18 hours. The solvent was evaporated and the residue was azeotroped with cyclohexane, giving rise to an oil, which was diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with a 10% aqueous sodium hydroxide solution and water, dried (MgSO4) and evaporated, yielding the title compound, producing 46 g. A sample (5 g) was recrystallized from isopropanol, with the production of 2.5 g ® having a melting point of 93 ^ρ to 95 ⁹ .

Analysis of C ^ I ^ ^NO ^, in percentage: Verified: C 61.2; H 4.1; N 7.9 Calculated: C 61.0; H 4.0; N 7.9

(C) 2-Bromoethyl-5-nitrobenzofuran

N-bromosuccinimide (1.1 grams, 6.2 mmoles) was added, portion by portion, to a solution of 2-methyl-5-nitrobenzofuran (1.0 g, 5.6 mmole) and benzoyl peroxide (50 mg) in carbon tetrachloride (50 ml), eas

The reaction mixture was heated at reflux temperature for 6 hours in the presence of bright light. The reaction mixture was then cooled and filtered, and the filtrate was evaporated to dryness. The residue was recrystallized from petroleum ether, giving rise to the title compound, with a production of 0.75 g and a melting point of 96 ⁹ to 98 ⁹ .

Analysis of C ^ II ^ BrNO ^, in percentage:

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

N-Meti1-4-ni trophenethylamine (0.41 g, 2.3 mmol), 2-bromomethyl-5-nitrobenzofuran (0.66 g, 2.6 mmol), sodium iodide (0.39 g, 2.6 mmole) and potassium carbonate (0.36 g, 2.6 mmole) were heated at reflux temperature, in acetonitrile (5θ ml), for 8 days. The solvent was then evaporated, water was added and the mixture was extracted three times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO4) and evaporated, giving rise to a semi-solid which was recrystallized from isopropanol, giving the title compound, with the production of 380 mg.

• H R.m.n. (DMSO / TFA): = 8.75 (s, ll); 8.3 (d, Ui); 8.2 (d, 2H); 7.9 (d, lill); 7.6 (d, 2H); 7.45 (s, III); 4.75 (t, 2H);

3.2 (t, 2H); 2.9 (s, 2H); 2.5 (s, 3H).

Preparation 6 (a) 2- ^B romomethyl-6-nitrobenzofuran

N-bromosuccinimide (NBS) (1.11 grams, 6.2 mmol) was added to a solution of 2-methyl-6-nitrobenzofuran (1.00 g, 5.65 mmol) and azobisibutyronitrile (20 mg) in tetrachloride carbon, and the mixture was heated at reflux temperature for 1.5 hours in the presence of bright light. The solvent was then evaporated, and the residue was dissolved in methylene chloride, washed with water, dried (MgSO4), evaporated to dryness, and purified by column chromatography on silica, eluting with inethylene chloride / hexane (7,3) · The product-containing fractions were combined and evaporated, yielding the title compound, yielding 1.43 g. A Π-R.m.n. it clearly revealed that the product contained 20¾ of 2-dibromomethy 1-6-nitrobenzo.furan; nevertheless, it was not considered necessary to remove this substance and the product was used directly, without any purification.

(b) N-Methyl-N- (6-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamine

CH_

N-Meti1-4-nitrophene tylamine (0.84 g, ^, 7 mmol), 2-bromoine ti 1-6-nitrobenzofuran (1.2 g, 4.7 mmol), sodium iodide (0.7 g , 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) were heated in acetonitrile at reflux temperature for 18 hours. The cooled reaction mixture was then filtered and the filtrate was evaporated to dryness and purified by chromatography on silica, eluting with methylene chloride / hexane (1: 1), followed by methylene chloride / methanol ( 19: 1). The fractions containing the product were combined and evaporated, and the residue was treated with charcoal decolorizing in ethanol, to provide an oil, which solidified on standing. Recrystallization of the solid from ethanol / methylene chloride gave the title compound, with the production of 0.27 g and the melting point of 69 ² to 69.5 ^S.

C analysis

as a percentage:

Found: C 60.8; H 4.8; N 11.8

Calculated: C 60.8; H 4.8; N 11.8 • H.R.m.n. (0001 ^): ^ = 8.3 (s, Hl); 8.15 (dd, 1H); 8.1 (d, 2H); 7.55 (d, 1H); 7.35 (d, 2H); 6.65 (s, 1H); 3.8 (s, 21);

2.95 (t, 3H); 2.75 (t, 3H); 2.4 (s, 3H).

Preparation 7 (A) 2-Hydroxymet i 1- 3 - me t i 1- 5 -ni t r ob enzofuran

Diborane q _n ² > ^H 3

OH

1 Molar diborane in tetrahydrofuran (18.0 ml, 18.0 mmol) was added dropwise and slowly to a suspension of 3-methyl-5-nitrobenzofuran-2-carboxylic acid (1.1 g, 5 mmole) in tetrahydrofuran at 02. Stirring was continued at 02 ° for 3 minutes and then at room temperature for 18 hours at which point a second portion of diborane (5.0 ml) was added and the reaction mixture was sonicated for 2.5 hours. Then, methanol was carefully added to the reaction mixture, and the solvent was removed by evaporation. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate and dried (MgSO4), and the solvent was removed by evaporation in vacuo and was purified by column chromatography on silica, eluting with sodium chloride. methylene. The product-containing fractions were combined and evaporated, yielding the title compound, yielding 0.96 g. A sample was recrystallized from ethyl acetate, and had a melting point of 149® to 1502.

Analysis of Ο ^ θΗ ^ ΝΟ ^, in percentage:

Found: C 57.9; H 4.2; N 6.7

Calculated: C 58.0; H 4.4; N 6.8 (B) 2-Chlorornet i1-3-meti1-5-nit robenzofuran

Thionyl chloride (1.48 g, 12.4 mmol) was added dropwise and slowly to a solution of 2-hydroxymethyl-3-methyl-5-nitrobenzofuran (0.86 g, 4.15 mmol) ), in methylene chloride (10 ml) and pyridine (2 drops), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with water, the organic phase was separated, and the aqueous phase was extracted again with methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate and dried (Na ^ SO ^) h the solvent was evaporated to give

origin to the title compound, with the production of 0.93 g. A portion was recrystallized from ethanol and had a melting point of 1412 to 142 ^a .

Analysis of C ^ EgClNO ^, in percentage:

Found: C 52.95; H 3.7; N 6.0

Calculated: C 53.2; H 3.6; N 6.2

Preparation 8

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

N-Meti1-4-ni trophene tilamine (0.39 g, 2.15 mmol) and 2-chloromethyl-6 ~ nitroquinoline (θ, 4θ g, 2.1 mmol) were heated, at reflux temperature, in ethanol (30 ml) for 6 hours. The solvent was then evaporated, and the residue was diluted with 2M hydrochloric acid and extracted with methylene chloride. The water layer

it was only basified with aqueous sodium carbonate (at a pH of about 12) and extracted three times with methylene chloride. These last organic extracts were combined, dried (MgSO4) and evaporated to an oil, which was purified by column chromatography on silica, eluting with methylene chloride, containing methanol (0% to 1%). The product-containing fractions were combined and evaporated, giving rise to a solid, which was recrystallized from ethanol, giving the title compound, with a production of 0.21 g and a melting point of 10M to 1095 ⁹ .

as a percentage:

Found: C 62.4; 4.7; N 15.2

Calculated: C 62.3; H 4.95; N 15.3

Ή-R.m.n. (CDCl3): 8.9 (d, III); 8.5 (dd, III);

8.3-8.1 (m, 3H); 7.6 (d, IH);

7.35 (d, III); 3.95 (s, 2H); 3.0 (t, 2H); 2.8 (t, 21); 2.4 (s, 3Π).

Preparation 9

(á) 4-Methanesulfonamidophenethyl mesylate

ΓΓ OH CH ₃ SO ₂ CL _ THE ^^ OS0 ₂ CH ₃ y h ₂ n Pyridine Z J CH-SO, N H

Methanesulfonyl chloride (146.6 g, 1.28 mmol) was added dropwise and slowly to a solution of 4-aminophenethyl alcohol (82.3 g, 0.6 mol) in pyridine (700 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into water (700 ml), and the precipitate was collected by filtration, washed with water, dried and recrystallized from ethyl acetate, giving the title compound, with the production of 31 S ® the melting point from 1342 to 1362. Another 14.5 S of the product were obtained by concentrating the mother liquids in vacuo.

(b) N-Benzyl-N-ethyl-4-methanesulfonamidophenethylamine

OSOgCH ^ | PhCH ^ NHEt

H

4-methanesulfonamidophenethyl mesylate (10 g, 34 mmol) and N-ethylbenzylamine (10 ml, 67 mmol) were heated at reflux temperature in ethanol (80 ml) for 3 hours. The solvent was evaporated and the residue was taken up in 2M hydrochloric acid and was washed twice with methylene chloride. The aqueous layer was basified with sodium bicarbonate (at pH about 12) and was extracted with methylene chloride. This last organic extract was dried (MgSO4) and was evaporated, yielding an oil, which solidified when ground with diisopropyl ether. The solid was filtered off and discarded, and the filtrate was evaporated in vacuo, giving the title compound as an oil, yielding 4.4 g.

Ή-R.m.n. (CDCl ^): =

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, 3Ii) (c) N-Ethyl-4-methanesulfonamidophenethylamine

CH SO „N

CH „CH

N-Benzi1-Ν-ethyl1-4-methanesulfonamidophenethylamine (4.3 g, 12.9 mmol) was stirred under an atmosphere of hydrogen (50 psi = 344.7 KPa) in ethanol (50 ml) containing 10% Pd / C (0.5 g) for 5 hours. The mixture was then filtered and evaporated, and the residue was triturated with ether, giving the title compound with the production of 2.6 g and the melting point of 125 ⁹ to 128 ⁹ *

Rmn (CDCl ₃ / DMSO): = 7.06 (s, 4l), 4.9 (s, 2H); 2.86 (s, 21); 2.8 (s, 21); 2.65 (q, 2Il); 1.05 (t, 3H).

Preparation 10 (a) N-Methyl-N- (3-methyl-5-nitrobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine f ^H 3

N-Methyl-4-methanesulfonamidophenethylamine (1.66 g, 7.3 mmol) and 2-chloromethyl-3-methyl-5 "nitrobenzofuran (see Preparation 7B - 0.82 g, 3.6 mmol) were heated to temperature reflux, in ethanol (20 ml) for 3 hours. The solvent was then evaporated and the residue was purified by column chromatography, eluting with methylene chloride / hexane, followed by methylene chloride containing methanol (0% to 5%). The product-containing fractions were combined and evaporated, and the residue was recrystallized from ethanol, giving root to the title compound, with a production of 1.52 g and a melting point of 1249 _to 124.5 ² .

as a percentage:

Verified: 0 57.7; H 5.65; N 10.0

Calculated: 0 57.5; H 5.55; N 10.1

Ή-R.m.n. (CDCl3): = 8.45 (d, 1H); 8.25 (dd, 11); 7.5 (d, III); 7.2 (q, 4yl); 3.8 (s, 21);

3.05 (s, 3H); 2.9 (t, 2H); 2.75 (t, 2H); 2.4 (s, 3H ( _; 2.35 (s, 3H)).

I ί

I (b) N-Methyl-N- (3-niethyl-5 "aminobenzofur-2-ylmethyl) -4-methane sulfonamidophenylamine

The catalytic hydrogenation of the product of part (à) (o, 7 g), in a similar manner to that of Preparation 1 (C), with a reaction time of 4 hours, gave the title compound (0.65 g) .

Ή-NMR (CD ₃ 0d): ^ = 7.25 (m, 6H); 6.9 (d, 1H); 6.8 (dd, III); 3.8 (s, 2H); 2.95 (s, 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

N-Ethyl-4 — methanesulfonamidophenethylamine (see Preparation 9 (c) - 1.7 St Ί, θ mmole) and 2-chloromethyl-6-nitroquinoline (0.78 g, 4.1 mmole) were heated to reflux in ethanol (50 ml) for 4 hours. The solvent was then evaporated and the residue was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried (MgSO4) and evaporated and the residue was purified by column chromatography over silica, eluting with methylene chloride. The product-containing fractions were combined and evaporated, yielding the title compound, as an oil producing 0.56 g.

Ή-R.m.n. (0001 ^): ^ = 8.6 (d, III); 8.3-8.0. (M, 2: 1); 7.6 (d, 1H); 7.1 (s, 1H); 7.0 (s, 4h), ‘

3.9 (s ’, 2H); 2.9 (s, 2H); 2.7 (s, 21); 2.65 (q, 2H); 1.05 (t, 3H).

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

The product of part (a) (0.55 g) was hydrogenated catalytically, in a similar manner to that of Preparation 1 (c), but using Hg over 5% Pd over C, in ethyl acetate, at 15 p.s.i. (103.4 KPa), for 3 hours, giving rise to the title compound, with the production of 0.51 g.

Ή-Rmn (cDC1 ₃ ): 7.7 (d, lll); 7.5 (d, 1H); 7.15 (d, 1H); 6.9 (broad s, 5H); 6.65 (d, 1H); 3.75 (s, 2H); 2.95 (s, III); 2.6 (s, 4-H); 2.5 (q, 2H) j 0.95 (t, 3H).

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

2-Methyl-6-nitroquinoline (18.8 g) was stirred under a hydrogen atmosphere at 3θ psi (equivalent to 2θ6.8 KPa6) for 2 hours in an ethanol solution containing 5% Pd / C. The catalyst was then removed by filtration, the filtrate was evaporated to a small volume in vacuo, and the resulting precipitate was collected by filtration, washed with ethanol and ether, and dried, giving the title compound, with the production of 13.2 g and the melting point from 1882 _to 1892,

Analysis of ^Ο 1Ο ^Η 1Ο ^Ν ₂ 'as a percentage:

Found: C 75.7; H 6.4; N 17.6

Calculated: C 75.9; H 6.4; N 17.7 (b) 6-Methanesulfonamido-2-methylquinoline

methanesulfonyl chloride (6.2 ml) was added dropwise and slowly to a stirring solution of 6-amino-2-methylquinoline (12.5 g) in pyridine (100 ml), cooled to 5 ^ρ · Stirring was continued for 17 hours at room temperature. The pyridine was then removed by evaporation in vacuo. and the residue was diluted with aqueous sodium bicarbonate, and was extracted three times with methylene chloride. The combined organic extracts were dried (MgSO4) and evaporated in vacuo. giving rise to the title compound, with a production of 13.0 g and a melting point of 151 ^s to 153 ⁹ ·

Analysis ^for P® ^I '®® ^{n' Lo spleen} G®

Verified: C 55, ^ ·; H 5.2 N 11.6

Calculated: C 55.9; H 5.1 N 11.9 (c) 6-Motanosulfonamido-2-methylquinoline-1-oxide

m-chloroperbenzoic acid (MCPBA ”) (5.2 g) was added, portion by portion, to a solution of 6-methanesulfonamido-2-methylquinoline (6 g) in methylene chloride, and stirring was continued for 17 hours. The reaction mixture was then diluted with aqueous sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo, giving rise to a solid, which was recrystallized from ethanol, giving the title compound, with the production 1.6 g and the melting point from 2319 to 243 2.

Analysis of ^C ii ^H i2 ^N 2 ⁰ 3 ^S * ⁱⁿ P ^ercenta S ^in!

Found: C 52.5; H 4.95; N 11.0

Calculated: C 52.4; H 4.8; N 11.1 (D) 2-Chlorome t i1-6-methanes sulfonamidoquinoline

6-Methanesulfonamido-2-methiquinoline-1-oxide (1.65 g) and β-toluenesulfonyl chloride (1.72 g) were heated, under reflux, for 1 hour, in a solution of 1, 2-dichloroethane, and the reaction mixture was allowed to repoil at room temperature for 17 hours. The reaction mixture was then washed twice with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with methylene chloride containing methanol (0¾ to 1¾). The product-containing fractions were combined and evaporated, giving rise to a gum, which solidified when ground with ether. Recrystallization from toluene gave rise to the title compound, with the production of 0.75 S ^G with the melting point from ⁹ to 162 ⁹ .

Analyze

as a percentage:

Found: C 49.3; II 3.9; N 10.1

Calculated: C 48.8; H 4.1; N 10.35

Preparation 13 (a) 2-Chloromethyl-5-’nitrobenzo / ’* b_7thiophene

soci ₂

Pyridine

Was added dropwise and slowly thionyl chloride (1.0 ml) to a stirred mixture of 5 "nitrobenzoyl / ^- b ^ icfcno 7-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 ml). The solution was stirred at room temperature for 4 hours, and then it was washed with water, followed by an aqueous sodium bicarbonate solution, and then it was dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane gave rise to a solid which was crystallized from ethyl acetate, giving rise to the title compound (o, 73 g), with the melting point of HO ⁹ to 112 ⁹ , used directly in the phase Following.

(b) N-Methyl-N- / 5-nitro-2-benzo / ”b 7'i ^; i ^and nilmetil7-4-nitrophenethylamine

A mixture of the product from the previous step (a) (3.20 g), with N-methyl-4-nitrophenethylamine (2.52 g), anhydrous potassium carbonate (4.0 g) and acetonitrile (40 ml) was heated , under reflux, with stirring, for 20 hours, and then it was cooled and filtered. The residue was washed with acetonitrile, and the combined filtrate and washing solutions were evaporated, yielding an oil, which was chromatographed on silica gel. Elution with dichloromethane gave impurities first, and then the pure product. The product-containing fractions were evaporated, yielding the title compound (4.17 g), with a melting point of 76 ⁹ to 78 ² (from isopropanol),

as a percentage:

Found: C 57.8; H 4.4; N 11.1

Calculated: C 58.2; H 4.6; N 11.3 (C) N-Methyl-N- / 5-amino-2-benzo / “b 7 thienylmethyl7-4-aminophenethylamine

A mixture of the product of (b), the preceding (1.0 g) and stannous chloride dihydrate (6.07 g) in ethanol (100 ml), was heated, under reflux, for 8 hours, and then , was evaporated. An excess of a 20% aqueous sodium hydroxide solution was added and the mixture was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried (NagSO ^) and evaporated to an oil, which was chromatographed on silica gel. Elution with dichloromethane / methanol (99: 1) gave rise to impurities, and then a further elution with dichloromethane / methanol (98: 2) gave rise, after collection and evaporation of the appropriate fractions, to the product as an oil. (0.30 g), which was used immediately in the process of Example 6.

Preparation 14 (a) 4- / 2- (Methanesulfonyloxy) ethyl7-methanesulfonanilide

methanesulfonyl chloride (5θ ml) was added dropwise and slowly, over 0.5 hours, to a stirring solution of 4-aminophenethyl alcohol (41.15 g) in pyridine (350 ml ) at 02, The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then poured into water (700 ml) in which an orange solid crystallized. After filtration, the solid was dissolved in methylene chloride, dried over magnesium sulfate and filtered, and the filtrate was evaporated again. The crystallization of the resulting solid from ethyl acetate gave rise to the title compound, with the production of 45.5 g and the melting point from 1362 to 137 ² .

C analysis

as a percentage:

Found: C 40.6; H 5.2; N 4.9

Calculated: C 40.9; H 5.15; N 4.8 (b) 4- / 2- (Methylamino) ethyl / methanossuIfonanilide

CH ₂ CH ₂ NHCH ₃

To a solution of 4- / 2- (methanesulfonyloxy) ethyl 7 methanesulfonide (10.3 g) in ethanol (20 ml) was added a solution of methylamine in methylated methylated alcohol (30 ml 33% solution) · The mixture was heated , with stirring at 85 ^s , in a pressure vessel for 17 hours. After cooling, the resulting solution was evaporated to dryness, the residue was dissolved in water and the resulting solution was made basic by the addition of sodium hydroxide (1.4 g) in water (12 ml). Evaporation gave rise to an almost white solid, which was chromatographed on silica (Kieselgel 60 - Trademark) eluting with methylene chloride / inethanol (3: 1). The collection and evaporation of the appropriate fractions gave rise to an almost white solid (4.8 g), which crystallized from ethyl acetate / methanol, giving rise to the title compound with the product.

1.8

Analysis of

Verified:

ge with the melting point of 133 ⁹ to 135 ⁹ .

as a percentage:

C 52.5; H 7.1; N 12.2

Calculated: C 52.6; H 7.1; N 12.3

Claims (7)

CLAIMS: 1&. - Process for the preparation of a compound of the formula: (C ₁ -C ₄ alkyl) SO _the NH - (I) 1 z or a pharmaceutically acceptable salt thereof, where R is alkyl ^and "Het" is a group of the formula: - NHSO ₂ (alkyl where R ² is H, CH CH or CH ₃ ; characterized by; or θ ₂ ®5 ' ^and X ® ° »® ^{or in} 9 ^{u and} H or (A) if acylated from a compound of the formula -56 where R and C ^ -Cjp and -NH or -NHSOg (C ^ C ^ alkyl), "Het" is a group of formulas --- (Β) -I R ó alkyl where R and X are what was established in the preceding, and R is -NH,> ^or “NHSOg (C ^ -C ^ alkyl), with the proviso that R ^a and R are not both -NHS0 ₂ (C ^-C ^ alkyl); with a C 1 -C 4 -sulfonyl alkane chloride or bromide, or with a C 1 -C 4 -sulfonic alkane anhydride; or (b) a compound of the formula is reacted: (alkyl with a compound of the formula,: R ^d -CH _£ -Het and ο vel, ee ”Het are what remained another is a separate group established in the preceding being said process (à) or (b) optionally followed by the conversion of the product of formula (l) into a pharmaceutically acceptable salt. 2. A process according to claim 1 (b) characterized in that the leaving group is chlorine, bromine, iodine, benzenesulfonyloxy or toluenesulfonyloxy. 3-. Process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of an acid acceptor. Process according to any one of the preceding claims, characterized in that a compound of the formula (i) is prepared, wherein R is -NHSOgCH ^; R ^ and CII ^ or CgH ^; ^e ® ™ 5 ^ru P ° of the formula: - where R ² is H or CII ^, X position a or b of Het z and z and mule claim: 1 (á) for 0 or S; and R ^, g _Ue © is linked to -NHSO_CH_. 5 &. - Process, according to the preparation of a compound of the form NHSO-CH * Λ * 3 (ΙΑ) characterized by reacting N-methyl-N- (5-aminobenzofur ~ 2-yl-methyl) -4-aminophenethylamine with methanesulfonyl chloride, in the presence of an acid acceptor. 6th. Process according to claim 1 (a) or 1 (B) for the preparation of a compound of the formula: - / Γ \ -3 li CH ₃ SO ₂ NH— # V (ch ₂ ) ' ₂ - ⁿ -cb ₂ - 1 i --- (IB) -59 characterized by either (a) reacting N-methyl-N- (o-aminoquinol-2-ylmethyl) -4-aminophenethylamine with methanesulfonyl chloride, in the presence of an acid acceptor, or (b) reacting 4- / 2- (methylamino) ethyl7methanesulfonanilide with 2-chloromethyl-6-methanesulfonamidoquinoline. 7. A process according to claim 5 or 6, characterized in that the acid acceptor is pyridine. 8®. - Process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula (i), obtained according to claim 1, or a pharmaceutically acceptable salt thereof, is mixed with a diluent or a vehicle, pharmaceutically acceptable.