DD281599A5 - PROCESS FOR THE PREPARATION OF NEW SULPHONAMIDES - Google Patents

Abstract

The invention relates to a process for preparing novel sulfonamides of the formula and their salts, wherein R is NHSO 2 (C 1 -C 4 -alkyl), NH 2 or NO 2; R1 is C1-C4 alkyl; and "Het is a group of the formula wherein R2 is H, CH3 or C2H5; R3 is NHSO2 (C1-C4 alkyl), NH2 or NO2; and X is O, S or NR4, wherein R4 is or CH3, with the Condition that when one of the substituents R and R3 is NO 2, then the other is not NH 2. The compounds of the formula wherein R and R 3 are both NHSO 2 (C 1 -C 4 alkyl) are antiarrhythmic agents The remaining compounds of the formula (A) are synthetic intermediates, formulas {processes, preparation, sulfonamides, synthetic intermediates, antiarrhythmic, positive inotropic}

Description

is in which

R ^{2 is} H or CH ₃ , X is O or S, and R ³ attached to the a or b position of "Het" is NHSO ₂ CH ₃

 5. The method of claim 1 (A) for the preparation of a compound of formula

GH-SO ₂ NH-

OH,

(CH ₂ ) ₂ -N-CH ₂ ~

NHSO ₂ CH ₃

characterized by the reaction of N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine with methanesulfonyl chloride in the presence of an acid acceptor. 6. The method of claim 1 (A) or (B) for the preparation of a compound of formula

GH.

! J

(CH ₂ ) ₂ -N-CH

marked either by

(A) the reaction of N-methyl-N- (6-aminoquinol-2-ylmethyl) -4-aminophenethylamine with methanesulfonyl chloride in the presence of an acid acceptor or

(B) Reaction of 4- [2- (methylamino) ethyl] methanesulfonanilide with 2-chloromethyl-6-methanesulfonamidoquinoline.

7. The method according to claim 5 or 6, characterized in that the acid acceptor is pyridine.

Field of application of the invention

The invention relates to a process for the preparation of certain sulfonamides which are arrhythmic agents.

Characteristic of the known state of the art

The compounds of the invention extend the duration of the action potential in the myocardium and conductive tissue and thereby increase the refractoriness against premature stimuli.

Therefore, according to the classification of Vaugham Williams (Anti-Arrhythmic Action, E.M. Vaugham Williams Academic Press, 1980) they are class IM antiarrhythmic agents. They are effective in the atria, ventricles and conductive tissue both in vitro and in vivo and are therefore useful in the prevention and treatment of many different ventricular and

supraventricular arrhythmias, including atrial and ventricular fibrillation. Since they do not alter the rate at which the pulses are transmitted, they are less prone to induce or aggravate arrhythmias than current drugs (usually Class I), and also result in fewer neurological side effects. Some of the compounds also have some positive inotropic activity and are therefore particularly beneficial in patients with impaired cardiac pumping function.

Object of the invention

Thus, the invention provides compounds of the formula

_π 1

- N - CH ₂ - Het

and salts thereof, wherein R-NO _{21 is} -NH ₂ or -NHSO ₂ (C ₁ -C ₄ -alkyl); R ¹ is C ₁ -C ₄ -alkyl; and, Het * is a group of the formula

or

wherein R ^{2 is} H, CH ₃ or C ₂ H ₆ ; R ³ is-NO _2, -NH ₂ or -NHSO ₂ -

(C 1 -C ₄ -alkyl); and X is O, S or NR ⁴ wherein R ^{4 is} H or CH ₃ ; with the proviso that when one of the substituents R and R ^{3 is} -NO ₂ , the other is not -NH ₂ .

The compounds of formula (A) in which R and R ^{3 are} -NHSO ₂ - (C 1 -C ₄ -alkyl) have activity as antiarrhythmic agents. The remaining compounds are synthetic intermediates.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of new sulfonamides. Thus, the invention also provides antiarrhythmic agent cV formula

R ¹ (CH,) _ -N - CH ₉ - Het "I

and their pharmaceutically acceptable salts, wherein R is -NHSO ₂ (C ₁ -C ₄ -alkyl); R ^{1 is} C ₁ -C ₄ -AIM; and "Het" a group of the formula

or

wherein R ^{2 is} H, CH ₃ or C ₂ H ₆ ; R ³ is -NHSO ₂ (C 1 -C ₄ alkyl); and X is 0.6 or NR ⁴ wherein R ^{4 is} H or CH ₃ .

In the compounds (I), R is preferably -NHSO ₂ CH ₃ , R ¹ is preferably CH ₃ or C ₂ H ₆ , R ² is preferably H or CH ₃ , R ³ is preferably -NHSO ₂ CH ₃ , and X is preferably O or S.

The substituent R ³ is preferably in the 6- or 7-position when "Het" contains a quinolyl group and otherwise in the 5- or 6-position (ie, when the benzene ring is fused to a 5-membered heterocycle).

The preferred individual compounds have the formulas:

CH₃SO₂NH-> - (CHj)₂-N-CH₂- ^.JK ^ ^  (IA)

NHSO ₂ CH ₃

And CH ₃ SO ₂ NB

(IB).

The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts of acids which form du non-toxic pharmaceutically acceptable anions containing acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, Tartrate, citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate

 The salts can be prepared by customary techniques.

To determine the effects of the compounds on atrial refractoriness, guinea pig right hemiatrices were placed in a bath containing physiological saline and one end connected to a force transducer. The tissues were stimulated at 1 Hz using field electrodes. The effective refractory period (ERP) is measured by introducing premature stimuli (S ₂ ) after every 8th basal stimulus (S ₁ ). The S ₁ S ₂ coupling interval is gradually increased until S ₂ reproducibly elicits a propagated response. This is defined as ERP. Then the concentration of compound required to increase ERP by 25% (ED ₂₆ ) is determined. ERP is also measured on right guinea pig papillary muscles incubated in physiological saline. The muscles are stimulated at one end using bipolar electrodes and the propagated electrogram is recorded at the opposite end via a unipolar surface electrode. ERP is determined as above using the Extrastimulus technique. Transition time is obtained from a digital storage oscilloscope by measuring the interval between the stimulus artifact and the peak of the electrogram (ie the time the pulse takes to travel the length of the muscle).

Atrial and ventricular ERP data were also measured on anesthetized or non-anesthetized dogs by the extrastimulus technique with the atrium or right ventricle held at a constant pulse rate. The compounds of formula (I) may be administered alone, but in general will be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. They may be administered to patients suffering from arrhythmias as well as prophylactically to those who may develop arrhythmias. For example, they may be administered orally in the form of tablets containing diluents such as starch or lactose, or in capsules, alone or in admixture with diluents, or in the form of elixirs or suspensions containing flavoring or coloring agents. You can parenteral, ζ. Β. intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution containing other solutes, e.g. For example, it may contain sufficient salts or glucose to render the solution isotonic.

When administered to humans for curative or prophylactic treatment of cardiac diseases, such as ventricular or supraventricular arrhythmias including atrial and ventricular fibrillation, oral doses of the compound of formula (I) are expected to be in the range of 2 to 150 mg daily, up to 4 taken Single doses per day, for an average adult patient (70kg). Doses for intravenous administration are expected to be in the range of 1.0 to 20 mg per single dose, as needed. Cardiac arrhythmia is preferably treated intravenously to achieve a rapid decline to normal. Thus, for a typical adult patient, single tablets or capsules may contain from 2 to 50 mg of active compound in a suitable pharmaceutically acceptable vehicle or carrier. Changes may occur depending on the weight and condition of the person being treated, as known to the physician.

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

Further, the invention provides a method of preventing or reducing cardiac arrhythmias in man comprising administering to said human an effective amount of a compound of formol (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined above.

In addition, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, in particular for use as an antiarrhythmic agent. Furthermore, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or reduction of cardiac arrhythmias. The compounds of formula (I) can be prepared by the following general routes:

(1) The first route involves the acylation of a compound of formula (A) wherein R and / or R ^{3 is} -NH ₂ using a C 1 -C ₄ alkanesulfonyl chloride or bromide or a C 1 -C 12 alkanesulfonic anhydride. Of course, when R and R ^{3 are} both -NH ₂ , at least 2 equivalents of the acylating agent are required and, of course, R and R ^{3 are} the same in the final product.

The reaction is typically carried out at room temperature and optionally in the presence of an acid acceptor such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate. The presence of an acid acceptor is particularly 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 (I) can then be isolated and purified in a conventional manner.

The starting materials for this acylation are available in the usual way, for. As follows:

Q-CH ₂ -Het

K-CO ,, reflux, organic solution

2 3

medium

Het

catalytic hydrogenation, (eg H ₂ / Raney Ni / 344 kPa)

R ₂ -N-CH ₂ -Het

Round "Het" are as defined for formula (I), and Q is a separating group such as chlorine, bromine, iodine or methanesulfonyloxy.

(CH ₂ J ₂ -O. + RNH-CH ₂ -Het

K ₀ CO ,, reflux, organic solution

2 3

medium

₂ -N-CH ₂ Het

catalytic hydrogenation (eg H ₂ / Raney Ni / 344 kPa)

(CH ₂ ) ₂ -N-CH ₂ -Het

R, Het and Q are as defined in (a) above.

(c) The routes (a) and (b) can also be carried out using starting materials in which the substituent R ^{3 is} .Hot * nitro instead of C, -C ₄ alkanesulfonamido to form a dinitro intermediate which by catalytic hydrogenation in a diamino starting material, ie a starting material of formula (A) wherein R and R ^{3 are} both amino; and

-C ₄ "alkyl) SO ₃ NH- ^ \ - (CH ₂ ) ₂ NHR + Q-CH ₂ -Het (R ³ in Hat

Reflux, organic solvents

C ₄ alkyl) SO ₀

₂ -N-CH ₂ -Het (R.

catalytic hydrogenation (eg H ₂ / Raney Ni / 344 kPa)

^(C l ~ ^C ~ 4 ^{alkyl) SO} 2 ^NH

-M-CH ₂ -Hat (R

R is C ₁ -C ₄ alkyl, "Het" in the first step is a nitro-substituted heterocycle as defined for formula (A) and Q is a

separating group as defined in (a) above.

The starting materials used in the methods (a) to (d) are either known compounds or they can be

customary techniques are produced, for. By the techniques illustrated in the following preparations.

(2) The second route to compounds (I) can be illustrated as follows:

₁ -C ¹⁴

(CH ₀ ) NHR + Q-CH, -Het-> Verbin-22 2 ^ fertilize

or

(C, -C -alkyl) SO ₀ NH - ff \ - (CH ₀ ), -O. + R ¹ NH-CH-Het-> compound- ¹⁴ 2/2 2 2 fertilize (I)

R ¹ is C ¹ -C ₄ alkyl, "Het" is as defined for formula (I), and Q is a separating group such as chlorine, bromine, iodine, C ₁ -C ₄ alkylsulfonyloxy (preferably methanesulfonyloxy), The reaction is preferably carried out in an organic solvent to reflux temperature The reaction is preferably carried out under reflux The presence of an acid acceptor is optional, but highly useful when Q is Cl, Br or J. Typical acid acceptors are pyridine, triethylamine, potassium carbonate The starting materials are again known compounds or can be obtained in the usual way.

embodiments

The following examples, in which all temperatures are given in ° C, illustrate the preparation of the compounds of formula (I).

Example 1 N-methyl-N- (3-methyl-5-methanesulfonamylbenzofur-2-ylmethylM-methanesulfonamydophenethylamino

CH ₃ SO ₂

Methanesulfonyl chloride (0.21 g, 1.85 mmol) was added to a solution of N-methyl-N- (3-methyl-5-aminobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine (see Preparation 1OB, 0.78 g, 1 , 68 mmol) in pyridine (7 ml), and then the solution was stirred at room temperature for 60 hours. The solvent was evaporated and the residue was triturated with toluene. The toluene was decanted, the residue was stirred with aqueous sodium bicarbonate, and the precipitate was filtered off and recrystallized from methanol to give the title compound; Yield 0.38g; F. 142-143.5 ⁰ C. Analysis,%

found C 54.4 H 5.3 N 9.1

calculated for C ₂₁ H ₂₇ N ₃ O ₅ S ₂ C 54.2 H 5.85 N 9.0

Example 2 N-Methyl-N- (5-methanesulfonamydobenzofur-2-ylmethyl) -4-methanesulfonamldophenethylamine

NH,

Methanesulfonyl chloride (0.76 g, 6.6 mmol) was added to a solution of N-methyl-N- (5-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (see Preparation 3: 0.9 g, 3, OmMoI) in pyridine (25ml) and the mixture was stirred at room temperature for 18h. Then the solvent was evaporated and the residue was diluted with aqueous sodium bicarbonate and extracted 3 times with methylene chloride. The combined organic extracts were dried (MgSO ₄ ) and concentrated, and the residue was purified by chromatography on silica eluting with ethyl acetate. The product-containing fractions were combined, concentrated, and the resulting solid was recrystallized from ethyl acetate / methanol to give the title compound; Yield 0.35g; F. 177-179 ⁰ C. Analysis,%

Found C 53.2 H 5.7 N 9.0

calculated for Cj ₀ H ₂ SN ₃ O ₆ Sj C 53.2 H 5.6 N 9.3

Example 3 N-methyl-N-1-B-methanulfonamydobenzoxazole-1-methyl-1-methanyl sulfonamide dithium / methylamine

H ₃ SO ₂ Cl, tyridine

CH-SO ₂ H ^J ι

Methanesulfonyl chloride (0.38 g, 3.3 mmol) and N-methyl-N- (5-aminobenzoxazol-2-ylmethyl) -4-aminophenethylamine (cf. Preparation 1C; 0.45 g, ', SmMoI) in pyridine (20 ml) after co-reaction gave conditions similar to those in Example 2 the title compound; Yield from ethanol 0.25g; F. 174-176 ⁰ C.

Analysis,%

found C 50.4 H 5.1 N 12.4

calculated for C ₁₉ H ₂₄ N ₄ O ₆ S ₂ C 50.4 H 5.35 N 12.4

Example 4 N-methyl-N- (6-methanesulfonamydobenzofur-2-ylmethyl) -4-methanesulfonamidophenethylamine

Methanesulfonyl chloride (0.21 g, 1.8 mmol) and N-methyl-N- (e-aminobenzofur-2-ylmethyl) -4-aminophenethylamine (cf. Production 2; 0.24g, 0.82mmol) in pyridine (3ml), after co-reaction, gave conditions similar to those in Example 2 the title compound as an oil; Yield 0.18g.

Analysis,%

found C 53.0 H 5.7 N 9.1

calculated for C ₂₀ H ₂₅ N ₃ Oj ₁ S ₂ C 53.2 H 5.6 N 9.3

Example 5 N-r / ethyl-N-fe-methanesulfonamido-bis-ol-ylmethyl-1-methanesulfonamydophenethylamine

Methanesulfonyl chloride (0.15 g, 1.3 mmol) and N-methyl-N- (e-aminoquinol-2-ylmethyl) -4-aminophenethylamine (see Preparation

4; 0.17g, 0.37mmol) in pyridine (20ml) gave, after co-reaction under similar conditions, win in Example 2

Title compound; Yield 0.70 g from ethyl acetate; F. 163-165X.

Analysis,%

found C 54.3 H 5.45 N 12.1

calculated for C ₂ ) H ₂₆ N ₄ O ₄ SC 54.5 H 5.7 N 12.1

Example β N-Methyl-N- [5-methanesulfonamido-2-benzo [b] thlenyl-methyl-methane-sulfonamidophenethyl-amine

CH

NHSO ₂ CH ₃

CH ₃ SO ₂ NH

The treatment of N-methyl-N- (5-amino-2-benzo [b] thienylmethyl) -4-aminophenethylamine (0.26 g, see Preparation 13) Methanesulfonyl chloride (0.23g) in pyridine according to the method of Example 2 gave the title compound, (0.167g); F. 175-

Analysis,%

found C 50.99 H 5.39 N 8.93

calculated for C ₂₀ H ₂₅ N ₃ O ₄ S ₃ C 51.37 H 5.39 N 8.99

Example 7 N-Ethyl-N-IE-methanesulfonamido-bromo-1-methyl-1-methanesulfonamidophenethylamine hydrochloride

CH ₃ SO ₂ NH

Methanesulfonyl chloride (0.1 g, 1.29 mmol) was treated with N-ethyl-N- (6-aminoquinol-2-ylmethyl) -4-

methanesulfonamidophenethylamine (see Preparation 11B, 0.51 g, 1.23 mmol) in pyridine, similar to the procedure of Example 2, to give the title compound free base as a gum. The gum was dissolved in ethyl acetate and the solution was diluted with ethereal hydrogen chloride and concentrated to dryness. The residue was triturated with one to give the title compound as a foam; Yield 0.06g; F. 96 ° C.

Analysis,%

Found C 50.2 H 5.5 N 10.0

calculated for CjjHjsN ^ Sj-HCl-HjO C 49.75 H 5.9 N 10.5

Example 8 N-fB-Methanesulfonamide diazolylmethyl-N-methyl-methylsulfonamidophenethylamine

ClCH

CH ₃ SO ₂

NHSO ₂ CH

4- [2- {methylamino) ethyl} methanesulfonanideide (0.228 g, 1 mmol, see Preparation 14 (B)) and 2-chloromethyl-6-methanesulfonamidoquinoline (0.13 g, 0.5 mmol, see Preparation 12 [D. The solvent was evaporated under vacuum and the residue was dissolved in methylene chloride, washed with water, dried (MgSO ₄ ), filtered and concentrated in vacuo The resulting gum was purified by column chromatography The resulting fractions were combined and concentrated under vacuum to a foam which crystallized from ethanol, yield of the title compound 0.45g, mp 165-166 °, confirmed by spectroscopy identical to the product of example 5. the following preparations, in which all temperatures are in angegeoen ⁰ C, illustrate the preparation of novel starting materials:

Production 1

(A) 2-Chloromethyl-5-n-nitrobenzoxazole

NH.HCl

'OH OEt

2-Amino-4-nitrophenol (10g, 65 mmol) and ethyl chloroacetimidate hydrochloride (15.4 g, 97.5 mmol) were heated to reflux in ethanol (100 mL) for 18 h. Then the solvent was removed by evaporation under vacuum and the residue was recrystallized from ethanol to give the title compound; Yield 9.0g; F. 216-217 ⁰ C. Analysis,%

found C 45,12 H 2,3 N 13,25

calculated for C ₈ H ₆ CIN ₂ O ₃ C 45.2 H 2.4 N 13.2

3) N-methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenethylamino n

2-chloromethyl-5-nitrobenzoxazole (2.85 g, 13.4 mmol), N'-methyl-4-nitrophenethylamine (JOC, [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 refluxed in acetonitrile (50 ml) 3d. Then the solvent was evaporated, the residue was diluted with water and extracted 3 times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO ₄ ), filtered and concentrated to dryness. The resulting oil was diluted with ether and the supernatant decanted and evaporated to dryness to give an orange solid, cisopolyrystallized from isopropanol to give the title compound; Yield 0,80g.

'H-NMR (CDCl ₃ ): δ 8.6 (d, 1 H), 8.3 (dd, 1 H), 8.1 (d, 2 H), 7, C (d, 1 H), 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-amyl, topazoxazol-2-ylmethyl) -4-aminophenethylamine

N-Methyl-N- (5-nitrobenzoxazol-2-ylmethyl) -4-nitrophenothylamine (0.73g, as in moles) in ethanol (50ml) containing Raney nickel (0.1g) was added under a hydrogen Atmosphere (344,7 \ t? a) stirred for 18 h; Thereafter, analysis by thin layer chromatography showed that all starting material was consumed (silica chromatography plates using methylene chloride / methanol (19: 1) as solvent). The reaction mixture was filtered and concentrated to give an oil which was azeotroped with toluene and triturated with ether. The decanted ether was concentrated to give the title compound as an oil which was used directly without further purification; Yield 0.45g

'H NMR (CDCl ₃ ): δ 7.25 (d, H), 6.95 (dd, 3H), 6.65 (dd, 1H), 6.6 (d, 2H), 3 , 8t; (s, 2H), 2.7 (s, 4H), 2.4 (s, 3H).

Preparations 2 bit 4

The compounds of Herste boys 2 and 3 were similar to the preparation 1 (C) by reduction of the corresponding dinitro compounds (see Preparations β and 5). ij / Raney / Ni / ethanol / 344.7 kPa / room temperature using reaction times of 4 and 17 hours, respectively. The compound of Preparation 4 was prepared similarly to Preparation 1 (C) but using H ₂ / Pd / C in ethanol at 206.8kPa for 3h with the relevant dinitro starting material being the subject of Preparation 8.

CH,

NO ₂ -

, -N-CH ₂ -Bet'-NO ₂

NH.

CH.

₂ -N-CH ₂ -Het '

Production no.

-Het'-NO,

-Het'-NH,

¹ H-NMR

8 _(CDCl3) - 7.25 <d. IH); 6.95 (d, 2H); 6.75 (β, IE.,; 6.65 (s, IH); 6.6 (d, 2H): 6.4 (eH); 3.65 (β.2Η); 2.6 (2.6) m.AH); 2,3 (see 3H).

S (DMSO / TFA) - 7.75 (i.e., 2H); 7.3 (m 5H); 4.7 (i.e., 2H); 3,4 (q, 4H); 2.85 (β, 3Η).

Production 5

(A) 4- (isopropylldiamineoxy) nitrobenzene

iB

Λ,

CH.

A solution of propanone oxime (30 g, 0.4 mol) in dry tetrahydrofuran (300 ml) slowly became a suspension Sodium hydride (10.8 g, 0.45 mol) in dry tetrahydrofuran (50 ml). After completion of gas release were Dimethyl sulfoxide (100 ml) and 4-fluoronitrobenzene (57.85 g, 0.41 mol) were added and the reaction mixture was added for 2 h Room temperature stirred. Then the reaction mixture was poured into water and extracted 3 times with ether. The

combined ethereal extracts were washed with water, dried (MgSO ₄ ) and concentrated to give the title compound, which was granulated in hexane and filtered; Yield 67g. A sample (7 g) was recrystallized from ethanol; Yield 5g;

F. 104-106 ° C.

Analysis,%

found C55.6 H 5.05 Ί 14.35

calculated for C ₉ H ₁₀ N ₂ O ₃ C 55.7 H 5.2 N 14.4

(B) α-Methyl-S-n-nitrobenzofuran

HCOOH / HCl

I i

4- (lsopropylidenaminoxy) nitrobenzene (60g, 0,309MoI) was added to glacial acetic acid (530 ml), the gaseous hydrogen chloride (25g) was added and the mixture was heated to 100 ⁰ C 18h. The solvent was evaporated and the residue was washed with

Cyclohexane subjected to azeotrope formation; this gave an oil which was diluted with water and 3 times with methylene chloride

was extracted. The combined organic extracts were washed with 10% aqueous sodium hydroxide solution and water, dried (MgSO ₄ ) and concentrated to give the title compound; Yield 46g. A sample (5 g) was taken

Isopropanol recrystallized; Yield 2.5g; F. 93-95 ⁰ C.

Analysis,%

found C 61.2 H 4.1 N 7.9

calculated for C ₉ H, NO ₃ C61.0 H4.0 N7.9

(C) 2-Bromomethyl-5-nitrobenzofuran

N-bromosuccinimide, ° 2 ^N

Benzoyl peroxide

N-bromosuccinimide (1.1 g, 6.2 mmol) was added portionwise to a solution of 2-methyl-O-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 and filtered, and the filtrate was concentrated to dryness. The residue was recrystallised from Petroiethe to give the title compound; Yield 0.75g; F. 95-98 ⁰ C. Analysis%

found C41.7 H2,4 N5,3

calculated for C ₉ H ₆ BrNO ₃ C 42.2 H 2.4 N 5.5

(D) N-methyl-N- (5-nitrobenzyl-2-ylmethyl) -4-nitrophenetltylamine

N-methyl-4-nitrophenethylamine 60.41 g, 2.3 mmol), 2-3rommethyl-5-nitrobenzofui (0.66 g, 2, BmMoI), sodium iodide (0.39 g, 2.6 mmol) and potassium carbonate (0, 36 g, 2.6 mmol) were heated in acetonitrile (50 ml) at 8 ° reflux temperature. Then the solvent was evaporated, water was added and the mixture was extracted 3 times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO ₄ ) and concentrated to give a semi-solid which was recrystallised from isopropanol to give the title compound; Yield 380mg.

'H-NMR (DMSCTrA): δ 8.75 (s, 1H), 8.3 (, 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 ).

Production β

(A) 2-Bromomethyl-6-nirirobenzofuran

N-bromosuccinimide (.NBS *) (1.11 g, 6.2 mmol) was added to a solution of 2-methyl-6-nitrobenzofuran (1.00 g, 5.65 mmol) and azobisisobutyronitrile (20 mg) in carbon tetrachloride, and the mixture was heated at reflux temperature for one hour in the presence of bright light. The solvent was evaporated and the residue was dissolved in methylene chloride, washed with water, dried (MgSO ₄ ), concentrated to dryness and purified by column chromatography on silica eluting with methylene chloride / hexane (7: 3). The product-containing fractions were combined and concentrated to give the title compound; Yield 1.43g. The ri-NMR data clearly showed that the product contained 20% 2-dibromomethyl-6-nitrobenzofuran, but it was not considered necessary to remove it and the product was used directly without further purification

 (B) N-methyl-N- (6-n-trobenzoxazol-2-ylmethyl) -4-n-trophenethylamino

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 mmoles) and potassium carbonate (0.71 g, 5.2 mmoles) were heated in acetonitrile at reflux temperature for 18 hours. The cooled

The reaction mixture was then filtered and the filtrate concentrated to dryness and purified by chromatography Silica eluting with methylene chloride / hexane (1: 1) followed by methylene chloride / methanol (19: 1). The

Product-containing fractions were combined and concentrated, and the residue was treated with decolorizing animal charcoal in ethanol to give an oil which solidified on standing. Recrystallization of the solid from ethanol / methylene chloride gave the title compound; Yield 0.27g; F. 69-69.5 ^c .

Analysis,%

found C 60.8 H 4.8 N 11.8

calculated for C ₁₈ H ₁₇ N ₃ O ₅ C60.8 H4,8 N11,8

Ή-NMR (CDCl ₃ ): δ 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),

Production 7

(A) 2-Hydroxymethyl-3-methyl-5-n-nitrobenzofuran

CH.

1M Diborane in tetrahydrofuran (18.0ml, 18%, OmMoI) was added dropwise to a suspension of 3-methyl-5-n-benzo-furan-2-carboxylic acid (1.1g, 5mmol) in tetrahydrofuran at 0 ° C. Ls was stirred at ⁰ ° C. for a further 30 minutes and then at room temperature for 18 hours, then 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 evaporated. The residue was taken up in ethyl acetate, washed with aqueous sodium carbonate, dried (MgSO ₄ ), the solvent was removed by evaporation under vacuum and purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and concentrated to give the title compound; Yield 0.96g. A sample was recrystallized from ethyl acetate; F. 149-150 ° C. Analysis,%

found C 57.9 H 4.2 N 6.7

calculated for C ₁₀ H ₉ NO ₄ C 58.0 H 4.4 N 6.8

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

CH 0, N. ^ f ^ ^ " ³ _socl

Thionyl chloride (1.48g, 1.24 mmol) was added dropwise to a solution of 2-hydroxymethyl-3-methyl-5-nitrobenzofuran (0.86 g, 4.15 mmol) in methylonchloride (10 mL) and pyridine (2 drops), and the Mixture was stirred at room temperature for 24h. Then the reaction mixture was diluted with water, the organic phase was separated and the aqueous phase re-extracted with MeVhylerxhlorid. The combined organic phases were washed with aqueous sodium bicarbonate, dried (Na ₂ SO ₄ ), and the solvent was evaporated, leaving the title compound; 0.93g. One part was recrystallized from ethanol; F. 141-142 ⁰ C

 Analysis,%

found C 52.95 H 3.7 N 6.0

calculated for Ci ₀ H ₈ CINO ₃ C 53.2 H3 6 N 6.2

PREPARATION 8 N-Methyl-N- (6-nlt.oquinol-2-ylmethylM-nitrophenethylamino

CH ₂ CH ₂ NHCH ₃ + ClCH ₂

N-methyl-4-nitrophenethylamine (0.39 g, 2.15 mmol) and 2-chloromethyl-6-nitroquinoline (0.40 g, 2.1 mmol) were heated to reflux in ethanol (30 mL) for 6 h. Then, the solvent was evaporated and the residue was diluted with 2m hydrochloric acid and extracted with methylene chloride. The aqueous layer was basified with aqueous sodium carbonate (to pH ~ 12) and extracted 3 times with methylene chloride. These latter organic extracts were combined, dried (MgSO ₄ ) and concentrated to an oil which was purified by column chromatography on silica eluting. Was cleaned. With methanol-containing (0% to 1% oil) methylene chloride. The product-containing fractions were combined and concentrated to a solid which was recrystallised from ethanol to give the title compound; Yield 0.21 g; F. 104-105 ⁰ C.

Analysis,%

found C62.4 H4,7 N 15,2

calculated for C ₁₁ Hi (N ₄ O ₄ C62.3 H4,95 N 15.3

'H NMR (CDCl ₃ ): δ 8.9 (d, 1H), 8.5 (dd, 1H), 8.3-8.1 (m, 3H), 7.6 (d, 1H), 7.35 (d, 1H), 3.95 (s, 2H), 3.0 (t, 2H), 2.8 (t, 2H), 2.4 (S. 3 H).

PREPARATION 9 (A) (4-Methanesulfonamidophenylethyl mesylate

OH

CH ₃ SO ₂ Cl

pyridine

CH ₃ SO ₂

Methanesulfonyl chloride (146.6 g, 1.28 mol) was added dropwise to a solution of 4-aminophosphoethyl alcohol (82.3 g, 0.6 mol) in pyridine (700 mL) and the mixture was stirred at room temperature for 18 h. Then, the reaction mixture was poured into water (700 ml), and the precipitate was filtered off, washed with water, dried and recrystallized from ethyl acetate to give the title compound; Yield 31 g; F. 134-136 ⁰ C. 14.5 g more product was obtained by concentrating the mother liquors under vacuum.

(B) N-benzyl-N-ethyl-4-methansulfonamldophenethylamln

OSO ₂ CH ₃

CH ₃ SO ₂

PhCH NHEt

CH ₃ SO ₂

4-Methanesulfonamidophenthyl mesylate (10g, 34 mmol) and N-ethylbenzylamine (10 ml, 67 mmol) were heated to reflux in ethanol (80 ml) for 3 hours. The solvent was evaporated, the residue was taken up in 2m hydrochloric acid and washed twice with methylene chloride. The aqueous layer was basified with sodium carbonate (to pH ~ 12) and extracted with methylene chloride. The latter organic extract was dried (MgSO ₄ ) and concentrated to an oil which solidified on trituration with diisopropyl ether. The solid was filtered off and discarded and the filtrate concentrated under vacuum to the title compound as an oil; Yield 4,4g

'H-NMR (CDCl ₃ ): 57.2 (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-ethylene-4-methanesulfonamidophenethylamine

CH., CH

CH, SO "N

CH ₂ CH ₃

CH ₃ SO ₃ NH

N-Benzyl-N-ethyl-4-methanesulfonamidophenethylamine (4.3 g, 12.9 mmol) was stirred under a hydrogen atmosphere (344.7 kPa) in ethanol (50 mL) containing 10% Pd / C (0.5 g) for 5 h touched. The mixture was filtered, concentrated and the residue was triturated with ether to give the title compound; Yield 2.6g; F. 125-128 ° C

 NMR (CDCl3 / DMSO): 57.06 (s, 4H), 4.9 (s, 2H), 2.86 (s, 2H), 2.8 (s, 2H), 2.65 (q, 2H ), 1.05 (t, 3H).

PREPARATION 10 (AIN-methyl-N-IS-methyl-S-nltrobenzofur ^ -ylmethylM-methanesulfonamldophenethylamino

CH ₃ SO ₂ N

CH ₃ SO ₂ N

N-methyl-4-methanesulfonamidophenethylamine (1.66 g, 7.3 mmol) and 2-chloromethyl-3-methyl-5-nitrobenzofuran (cf.

Preparation 7B; 0.82 g, 3.6 mmol) in ethanol (20 mmol) were heated at reflux for 3 h. Then the solvent was evaporated and the residue purified by column chromatography on silica eluting with methylene chloride / hexane (4: 1) followed by methylene chloride containing methanol (0% to 5%). The product-containing fractions were combined and concentrated, and the residue was recrystallized from ethanol to give the title compound; Yield 1.52g;

124 to 124.5 F. ⁰ C.

Analysis,%

found C57.7 H5.65 N 10.0

calculated for C ₂₀ H ₂₃ N ₃ O ₆ SC 57.5 H 5.55 N 10.1

¹ H-NMR (CDCl ₃ ); 68.45 (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

(B) N-Methyl-N- (3-methyl-5-amlnobenzofur-2-ylmethyl) -4-methansulfonamldophenethylamln

(CH ₂ J ₂ -N (CH ₃ )

H ₂ / Raney Ni

CH SO NH

CH ₃₎ -CH

NH-

Catalytic hydrogenation of the product of Part IA) (0.7 g) similar to Preparation 1 (C) with a reaction time of 4 h gave the title compound (0.65 g).

¹ H-NMR (CD ₃ OD): 67.25 (m, 6H), 6.9 (d, 1 H), 6.8 (cM 1H.), 3.8 (s, 2H), 2, 95 (s, 3H), 2.9Im, 2H); 2.7 (m, 2H) 2.4 (s, 3H), 2.35 (s, 3H).

PREPARATION 11 (A) N-Ethyl-N- (6-n-hydrochlorol-2-ylmethyl) -4-methanesulfonam) dophenethylamine

CH ₃ SO ₂

CH ₃ SO ₂

N-ethyl-4-methanesulfonamidophenethylamine (see Preparation 9 (C); 1.7g, 7, OmMoI) and 2-chloromethyl-6-6-nitroquinoline (0.78g, 4.1mmol) were dissolved in ethanol (50ml). 4h heated to reflux temperature. Then the solvent was evaporated and the residue was diluted with aqueous sodium carbonate and extracted with methylene chloride. The organic layer was dried (MgSO ₄ ), concentrated and the residue purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and concentrated to give the title compound as an oil; Yield 0.56g.

'H-NMR (CDCl3): 58.6 (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).

(BIN-ethyl-N-ie-amlnochlnol ^ -ylmethylM-methansulfonamldophenethylamln

CH ₃ SO ₂ NH

H ₂ / Pd / C

CH ₃ SO ₂ NH- / - - (CH ₂ )., -

" ^approx

The product from part (A) (0.55g) was similar to Preparation 1 (C), but using H ₂ over 5% Pd on C in

Ethyl acetate was catalytically hydrogenated at 103.4 kPa for 3 h to give the title compound (0.51 g).

'H NMR (CDClI): 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, 3 H).

PREPARATION 12

(A) 6-Amino-2-methylquinoline

2-Methyl-6-nitroquinoline (18.8 g) was added under a hydrogen atmosphere of 206.8 kPa for 2 h in a 5% Pd / C

Stirred ethanol solution. The catalyst was filtered off, the filtrate was concentrated in vacuo to a small volume and the resulting precipitate was filtered off, washed with ethanol and ether and dried to the title compound;

Yield 13.2g; F. 188-189 '.

Analysis,%

found C75.7 H6,4 N 17,6

calculated for C _lo H, oN ₂ C75.9 H6,4 N17.7

(Bie-Methansulfonamldo ^ -methylchinolin

2 CH ₃ SO ₂ Cl

pyridine

Methanesulfonyl chloride (6.2 ml) was added dropwise with stirring to a solution of 6-amino-2-methylquinoline (12.5 g) in pyridine (100 ml), cooled to 5 °. It was stirred for a further 17 h at room temperature. The pyridine was then evaporated in vacuo, the residue was diluted with aqueous sodium bicarbonate and extracted 3 times with methylene chloride. The combined organic extracts were washed, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound; Yield 13.0g; F.151-153 ° C

 Analysis,%

found C 55.4 H 5.2 N11.6

berechnetfürC "H _n N ₂ O ₂ S C55,9 H5,1 N11.9

(C) e-methanesulfonyl-2-fonamldo methylchinolln-1-oxld

M-chloroperbenzoic acid ("MCPBS") (5.2g) was added portionwise to a solution of 6-methanesulfonamido-2-methylquinoline (6g) in methylene chloride and stirring was continued for 17h then the reaction mixture was diluted with aqueous sodium carbonate and the organic The aqueous layer was extracted with methylene chloride, the combined organic layers were washed with aqueous sodium carbonate, dried (MgSO ₄ ), and added under vacuum to a solid, which was recrystallised from ethanol to give the title compound, yield 1.6; 241-243 ⁰ C

 Analysis,%

found C52.5 H4.95 N 11.0

calculated for CiHuNjOaS C52.4 H4,8 N11.1.

(D) 2-chloromethyl-6-methansulfonamidochinolin

H ASO ₂ CH ₃

ISO ₂ CH ₃

p-toluenesulfonyl

chloride ClCH

6-Methanesulfonamido-2-methylquinoline-1-uxide (1.65 g) and p-toluenesulfonyl chloride (., 72 g) were refluxed in 1,2-dichloroethane solution for 1 hour, and then the reaction mixture was allowed to stand at room temperature for 17 hours. The reaction mixture was washed twice with aqueous sodium carbonate, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography on silica. Elute with methanol-containing (0% to 1%) methylene chloride purified. The product-containing fractions were combined and concentrated to give a gum which solidified on trituration with ether. Recrystallization from toluene gave the title compound; Yield 0.75g; F. 160-162 °. Analysis,%

found C49.3 H3.9 N 10.1

calculated for C _n H ,, N ₂ CIS C 48,8 H 4,1 N 10,35

PREPARATION 13 (A) 2-Chloromethyl-5-nitrobenzo / b / thiophene

HIGH

SCCl

pyridine

Thionyl chloride (1.0 mL) was added dropwise with stirring to a mixture of 5-niirobenzo / b / thiophene-2-methanol (1.0 g) and pyridine (2 drops) in dichloromethane (10 mL). The solution was stirred at room temperature for 4 h and then washed with water, followed by aqueous sodium carbonate solution and then dried (Na ₂ SO ₄ ). The solvent was evaporated and the residue chromatographed on silica gpf. Elution with dichloromethane gave a solid which was crystallized from ethyl acetate to give the title compound (0.73g); F. 110-112 ⁰ C; which was used directly in the next slush.

(BLN-methyl-N-IS-nitro ^ benzo / b / thienylme ^ iylM-nitrophenethylamln

.NO,

ClCH

K ₂ CO ₃

A mixture of the product from part (A) above (3.20g), N-methyl-4-nitrophenethylamine (2.52g), anhydrous potassium carbonate (4.0g) and acetonitrile (40ml) was refluxed with stirring for 20h and then cooled and filtered.

The residue was washed with acetonitrile and the filtrate and washings were combined and concentrated to give an oil which was chromatographed on silica gel. Elution with dichloromethane gave first an impurity, then the pure product. The product-containing fractions were concentrated to give the title compound (4.17 g); F. 76-78 ° C (Auslsopropanol).

Analysis,%

found C57.8 H4,4 N 11,1

calculated for CsH ₁₇ N ₃ O ₄ S C 58.2 H 4.6 N 11.3

(C) N -methyl-N- / 5-amino-2-benzo / b / thlenyltriethyl / 4-aminophenethylamine

SnCl,

A mixture of the product of (B) above (1.0g) and stannous chloride dihydrate (6.07g) in ethanol (100ml) was refluxed for 8 hours and then concentrated. An excess of 20% aqueous sodium hydroxide solution was added and the mixture extracted several times with dichloromethane. The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ) and concentrated to give an oil which was chromatographed on silica gel. Elution with dichloromethane / methanol (99: 1) ergi ύ an impurity, further elution with dichloromethane / methanol (98: 2), after collecting and concentrating the appropriate fractions, gave the product as an oil (0.30g) obtained directly in the method of Example 6 was used.

PREPARATION 14 (A) 4- / 2- (Methanesulfonyloxy) ethyl / methanesulfonanil

CH-.SO, C1

si /

Methanesulfonyl chloride (50 ml) was added dropwise over 0.5 h with stirring to a solution of 4-aminophenethyl alcohol (41.15 g) in pyridine (350 ml) at 0 ° C. The mixture was allowed to warm to room temperature and stirred overnight After filtration, the solid was dissolved in methylene chloride, dried over magnesium sulfate, filtered, and the filtrate was concentrated again, Crystallization of C9S solid obtained from ethyl acetate gave the title compound, 45.4 g; F. 13 & -13 / ° C Analysis,%

found C40.6 H 5.2 N 4.9

calculated for: C ₁₀ Hi ₆ NO ₆ S ₂ C40.9 H5.1o N4.8

(B) 4- / 2 - 'methylamino) ethyl / methansulfonanllid.

CH ₃ SO ₂ NH-

H ₂ CH ₂ OSO ₂ CH ₃

CH ₃ NH ₃

.-TV

To a solution of 4- / 2- (methanesulfonyloxy) ethyl / methanesulfonanilide (10.3 g) in ethanol (20 ml) was added a methylamine industrial methylated spirit solution (30 ml of a 33% solution). The first mixture was heated to 85 ° C. with stirring in a pressure vessel for 17 hours After cooling, the resulting solution was concentrated to dryness, the residue was dissolved in water and the resulting solution was added by adding sodium hydroxide (1.4 g) in water Concentration gave an off-white solid which was chromatographed on silica ("Kieselgel 60" trademark) eluting with methylene chloride / methanol (3: 1). Collecting and concentrating the appropriate 1 fractions gave a whitish solid (4.8 g) which was crystallized from ethyl acetate / methanol to give the title compound; 1.8 g; F. 133-135 ⁰ C

 Analysis,% found C52.5 H7.1 η 12.2

C52.6

H7,1

N 12.3

Claims (4)

claims: 1. ancestor for preparing a compound of the formula R ¹ t (C ₁ -C ₄ -AHCyI) SO ₂ NH-T ^x - (CH ₂ ) ₂ " ^N " ^GH 2 "' ^yeast or a pharmaceutically acceptable salt thereof, or optionally a pharmaceutical composition, wherein R ^{1 is} C ¹ -C ₄ alkyl; and "Het" is a group of the formula 2 MSO or MSO ₂ is in which R ^{2 is} H, CH ₃ or C ₂ H ₅ , and X is O, S or NR ⁴ , wherein R ^{4 is} H or CH ₃ , characterized by either (A) the acylation of a compound of the formula. * ^a -i _ V- (CH _O ) _O - H - ₂ ) ₂ CH ₂ - Het wherein R "is C ₁ -C ₄ alkyl, and" Het "is a group of the formula R ^u or wherein R ² and X are as defined above and R ^{b is} -NH ₂ or NHSO ₂ - (C 1 -C ₄ alkyl), with Condition that R ^a and R ^{b are} not both -NHSO ₂ (C ₁ -C ₄ alkyl); with a CrA alkanesulfonyl chloride or bromide or the like. C ^ d-alkanesulphonic anhydride; or (B) the reaction of a compound of the formula -AlKyI) SO ₂ M with a compound of the formula R ^- -CH ₂ -H ^ i, wherein one of the substituents R ^c and R ^{d is} -NHR ¹ and the other is a separating group and R ¹ and "Het" are as defined above; wherein process (A) or (B) is optionally followed by the conversion of the product of formula (I) into a pharmaceutically acceptable salt and optionally by mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. 2. The method according to claim 1 (B), characterized in that the separating group is chlorine, bromine, iodine, Ci-C ^ AIkansulfonyloxy or toluenesulfonyloxy. 3. The method according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of an acid acceptor. 4. The method according to any one of the preceding claims, characterized in that a compound of the forms! (I) is prepared, wherein R-NHSO ₂ CH ₃ is and
R is CH ₂ or C ₂ H ₅ and
"Het" a group of the formula