NO171635B - ANALOGY PROCEDURE FOR THE PREPARATION OF AN ALKYSULPHONAMIDOPHENYLALKYLAMINE N-SUBSTITUTED OVER A METHYL CHAIN WITH A HETEROCYCLIC GROUP - Google Patents

Abstract

Starting compounds and compounds with antiarrhythmic effect have the formula. and salts thereof,. wherein R is -NHSO 2 (C 1 -C 4 alkyl), -NH or -NO 2; is alkyl; and. "Het" is a group of the formula :. wherein H, CH or CH 2. R 1 -NHS 2 (C-Calcyl), -NH or -NO 2; and. X is O, S or NR, wherein R 1 is H or CH; with the proviso that when one of R and R 5 is -NO 2 then the other is not -NH 2. The compounds of formula (A), wherein both R and R e -NHSO (C compounds of formula (A) are starting compounds for the preparation of the active compounds. Preparation of the compounds (A) is also shown.

Description

The present invention relates to the production of certain sulfonamides which have antiarrhythmic action.

The compounds produced according to the invention prolong the duration of the action potential in the heart muscle and conducting tissue and thereby increase the resistance to premature stimuli. They are thus class III antiarrhythmic agents according to the classification of Vaughan Williams (Anti-Arrhythmic Action, E.M. Gaughan Williams, Academic Press, 1980). They are effective in atria, ventricles and conducting tissue, both in vitro and in vivo and are therefore useful for preventing and treating a wide number of ventricular and supraventricular types of arrhythmia including ventricular and ventricular fibrillation. Because they do not change the rate at which impulses are transmitted, they are less likely than currently used drugs (mainly Class I) to accelerate or worsen arrhythmias, and also have fewer neurological side effects. Some of the compounds also have a positive inotropic activity and are therefore particularly beneficial in patients with impaired heart pumping function.

According to the invention, antiarrhythmically active compounds are prepared with the formula

or a pharmaceutically acceptable salt thereof,

where R<1> is C1-C4 alkyl

and "Het" is a group with the formula:

or

where R<2> is H or CH3

and X is 0 or S.

The substituent -NHSO2/C1-C4 alkyl) is preferably in the 6- or 7-position when "Het" contains a quinolyl group, and in the 5- or 6-position otherwise (ie when the benzene ring is attached to a 5-membered heterocyclic group) .

The preferred single compounds have the formulas:

The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate , tartrate, citrate, gluconate, benzoate, methanesulfonate, besylate and p-toluenesulfonate salts. Also included are alkali metal salts, especially sodium and potassium salts. The salts are produced in a conventional manner.

To determine the effects of the compounds on atrial refractoriness, guinea pig right hemiatria were mounted in a bath containing physiological saline and one end was connected to a force transducer. The tissues were stimulated at 1 Hz using field electrodes. The effective nonreceptive period (ERP) is measured by introducing premature stimuli (S2) after every 8th base stimulus (Si). The S1S2 coupling intervals were gradually increased until S2 reproducibly elicited a propagated response. This is defined as ERP. The concentration of the compound required to increase the ERP by 25% (ED2s) is then determined. ERPs were also determined in guinea pig right papillary muscles incubated in a physiological saline solution. Muscles are stimulated at one end using bipolar electrodes and the propagated electrogram was recorded at the opposite end via a unipolar surface electrode. ERP is determined as above using an additional stimulus technique. The transmission time is obtained from a digital storage oscilloscope by measuring the interval between the artificially evoked stimulus and the peak of the electrogram (ie the time required for the pulse to travel along the entire length of the muscle).

Atrial and ventricular ERP values were also measured in anesthetized or sedated dogs by the additional stimulus technique, while holding the atrial or right ventricle at a constant beating rate.

The activity of some of the compounds prepared according to the following examples was determined as above, with the following results:

The compounds of formula (I) may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected having regard to the intended route of administration and standard pharmaceutical practice. They can be administered both to patients suffering from arrhythmia and also prophylactically to those who may be expected to develop arrhythmia. E.g. they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules, either alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring components. They can be injected parenterally, e.g. intravenously, intramuscularly or subcutaneously. For parenteral administration, they can best be used in the form of a sterile aqueous solution which may contain other dissolved components, for example sufficient salts or glucose to make the solution isotonic.

For administration to humans for curative or prophylactic treatment of heart diseases, such as ventricular and supraventricular arrhythmia, including atrial and ventricular fibrillation, it is expected that oral doses of the compounds of formula (I) will be in the range of 1 - 150 mg/day, taken in up to 4 divided doses per day for an average adult patient (70 kg). Doses for intravenous administration will be expected to be in the range of 1.0 - 20 mg per single dose as needed. A serious cardiac arrhythmia is preferably treated by intravenous administration to effect a rapid conversion to normal rhythm. Thus, for a typical adult patient, individual tablets or capsules may contain 2-50 mg of the active compound, in a suitable pharmaceutically acceptable carrier. This can be varied depending on the weight and condition of the patient being treated, which will be known to a doctor.

The compounds of formula (I) can be prepared by the following

general routes:

(1) The first route involves 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± -C 4 alkanesulfonic anhydride. When both R and R<3> are -NH3, obviously at least two equivalents of the acylating agent will be required, and consequently R and R<3> in the final product will also be the same. 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. 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 reaction are conventionally available, for example as follows:

(a)

R and "Het" are as defined in formula (I), and Q is a leaving group such as chlorine, bromine, iodine or methanesulfonyloxy.

(b)

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

(c) Routes (a) and (b) can be carried out using starting materials in which the substituent R<3> and "Het" is nitro instead of C₁-C₁ alkanesulfonamido, thus giving a di-nitro intermediate which can be reduced by catalytic hydrogenation to a di-amino starting material, i.e. a starting material of formula (A), in which both R and R<3> are amino. and (d) R is C1-C4 alkyl, "Het" in the first step is a nitro-substituted heterocyclic group as defined for formula (A), and Q is a leaving group as defined in (A) above. The starting materials used in the methods (a) - (d) are either known compounds or can be produced according to conventional techniques, for example by the techniques shown in the subsequent preparations. (2) The second route to the compounds (I) can be illustrated as follows: ;R<1> is C1-C4 alkyl, "Het" is as defined for formula (I), and Q is a leaving group such as chlorine, bromine , iodine, C1-C4 alkanesulfonyloxy (preferably methanesulfonyloxy), benzenesulfonyloxy or toluenesulfonyloxy. The reaction is typically carried out in an organic solvent at up to the reflux temperature. It is preferred to carry out the reaction under reflux treatment. The presence of an acid acceptor is optional, but is most useful when Q is Cl, Br or I. Typical acid acceptors are pyridine, triethylamine, potassium carbonate and sodium bicarbonate. The starting materials are again known compounds or can be obtained in a conventional manner. ;The following examples, in which all temperatures are in °C, illustrate the preparation of the compounds of formula (I): ;EXAMPLE 1 N-methyl-N-(3-methyl-5-methanesulfonamidobenzofur-2-ylmethyl)-4-methanesulfonamidophenethylamine Methanesulfonyl chloride (0.21 g, 1.85 myrtol) was added dropwise to a solution of N-methyl-N-(3-methyl-5-aminobenzofur-2-ylmethyl)-4-methanesulfonamidophenethylamine (see Preparation 10B - 0.78 g, 1.68 mmol) in pyridine (7 mL) and the solution was then stirred at room temperature for 60 h. The solvent was evaporated and the residue triturated with toluene. The toluene was decanted, the residue stirred with aqueous sodium bicarbonate, and the precipitate collected by filtration and recrystallized from methanol to give the title compound, yield 0.38 g, m.p. 142-143, 5°C. ;Analysis % ;Found: C 54.4; H 5.8; N 9.1 Calculated for C23H27N3O5S2: C 54.2; H 5.85; N 9.0. ;EXAMPLE 2 ;N-methyl- N-(5-methanesulfonamidobenzofur-2-ylmethyl)-4-methanesulfonamidophenethylamine ;;Methanesulfonyl chloride (0.76 g, 6.6 mmol) was added dropwise to a solution of N-methyl -N-(5-aminobenzofur-2-ylmethyl-)-4-aminophenethylamine (see Preparation 3 - 0.9 g, 3.0 mmol) in pyridine (25 mL) and the mixture was stirred at room temperature for 18 h. The solvent was then evaporated and the residue diluted with aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO 4 ) and evaporated, and the residue was purified by chromatography on silica eluting with ethyl acetate. ;The product containing fractions were combined, evaporated and the resulting solid was recrystallized from ethyl acetate/methanol to give the title compound, yield 0.35 g, m.p. 177-179<>C. ;Analysis % ;Found: C 53.2; H 5.7; N 9.0 Calculated for C20<H>25<N>3O5S2: C 53.2; H 5.6; N 9.3. ;EXAMPLE 3 ;N-methyl-N-(5-methanesulfonamidobenzoxazol-2-ylmethyl)-4-methanesulfonamidophenethylamine ;;Methanesulfonyl chloride (0.38 g, 3.3 mmol) and N-methyl-N-(5-minobenzoxazole-2 -ylmethyl)-4-aminophenethylamine (see Preparation 10 - 0.45 g, 1.5 mmol) in pyridine (20 mL) when reacted together under conditions similar to those in Example 2 gave the title compound in yield from ethanol 0.25 g, m.p. -, 174-176°C. ;Analysis % : ;Found: C 50.4; H 5.1; N 12.4 Calculated for C19H24N405S2: C 50.4; H 5.35; N 12.4. EXAMPLE 4 N-methyl-N-(6-methanesulfonamidobenzofur-2-ylmethylH-4-methanesulfonamidophenethylamine) Methanesulfonyl chloride (0.21 g, 1.8 mmol) and N-methyl-N-(6-aminobenzofur- 2-ylmethyl)-4-aminophenethylamine (see Preparation 2 - 0.24 g, 0.82 mmol) in pyridine (3 mL) when reacted together under conditions similar to those of Example 2 gave the title compound as an oil, yield 0.18 g. ;Analysis % ;Found: C 53.0; H 5.7; N 9.1 Calculated for C2oH25<N>3°5s2: c 53.2; H 5.6; N 9.3. ;EXAMPLE 5 ;N-methyl-N-(6-methanesulfonamidoquinol-2-ylmethyl)-4-methanesulfamidophenethylamine ;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) when reacted together under conditions similar to those in Example 2 gave the title compound, yield 0.70 g from ethyl acetate, mp read -ies^C. ;Analysis % ;Found: C 54.3; H 5.45; N 12.1 Calculated for C21H26N4O4S: C 54.5; H 5.7; N 12.1. ;EXAMPLE 6 ;N- metvl- N- r 5- methanesulfonamido-2- benzo Tb] thienylmet yl]-4-methanesulfonamidophenethylamine ;;Treatment of N-methyl-N-(5-amino-2-benzo[b]thienylmethyl-4-aminophenethylamine (0.26 g - see preparation 13) with methanesulfonyl chloride (0.23 g) in pyridine according to the method of Example 2 gave the title compound (0.167 g), m.p. 175-177°C. ;Analysis % : ;Found: C 50.99; H 5.39; N 8.93 Calculated for C20H25N3O4S3 C 51.37; H 5.39; N 8.99. EXAMPLE 7 N-ethyl-N-(6-methanesulfonamidoquinol-2-ylmethyl)-4-methanesulfonamidophenethylaminehydrochloride Methanesulfonyl chloride (0.1 g, 1.29 mmol) was reacted 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 in Example 2 gave the free base of the title compound as a gum. The gums were 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, yield 0.06 g, mp - 96°C. ;Analysis% : ;Found: C 50.2; H 5.5; N 10.0; Calculated for C22H28N4°4S2-1101-H20: c 49/75'" H 5.9; N 10.5. EXAMPLE 8 N-(6-methanesulfonamido-2-quinolylmethyl)-N-methyl-4-methanesulfonamidophenethylamine;4- [2-(Methylamino)ethyl]methanesulfonanilide (0.228 g, 1 mmol - see Preparation 14(B)) and 2-chloromethyl-6-methanesulfonamidoquinoline (0.135 g, 0.5 mmol) see Preparation 12(D) were heated in ethanol solution (5 mL) at reflux for 4 h. The solvent was then evaporated in vacuo and the residue dissolved in methylene chloride, washed with water, dried (MgSO 4 ), filtered and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride-containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated in vacuo to give a foam which crystallized from ethanol, yield of the title compound, 0.45 g, mp 165-166°C, confirmed spectroscopically to be identical to the product in example 5. The following preparations, in which all temperatures are given in °C, illustrate the preparation gen of new starting materials: ;Preparation 1 ;( A) 2-chloromethyl-5-nitrobenzoxazole ;;2-amino-4-nitrophenyl (10 g, 65 mmol) and ethyl chloroacetimidate hydrochloride (15.4 g, 97.5 mmol) was heated at reflux in ethanol (100 mL) for 18 h. The solvent was then removed by evaporation in vacuo and the residue recrystallized from ethanol to give the title compound, yield 9.0 g, m.p. 216-217"C. ;Analysis ;Found: C 45.15; H 2.3; N 13.25 Calculated for C8H5C1N2O3: C 45.2; H 2.4; N 13.2. ;( B) N- methyl-N-(5-nitrobenzoxazol-2-ylmethyl)-4-nitrophenethylamine;;2-chloromethyl-5-nitrobenzoxazole 2.85 g, 13.4 mmol), N-methyl-4-nitrophenethylamine (J.O.C., [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 under reflux in acetonitrile (50 ml) for 3 days. The solvent was then evaporated, the residue diluted with water and extracted three times with methylene chloride. The combined organic extracts were washed with water, dried (MgSO 4 ), filtered and evaporated to dryness. The resulting oil was diluted with ether and the supernatant decanted and evaporated to dryness to give an orange solid, which was recrystallized from isopropanol to give the title compound, yield 0.80 g.;' H- N. m. r. (CDC13): S 8.6 (d, 1H); 8.3 (dd, 1H); 8.1 ;(d, 2H); 7.6 (d, 1H); 7.35 (d, ;2H); 3.95 (s . ethylamine;;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 (344.7 kPa) for 18 hours, at which time thin-layer chromatographic analysis showed that all the starting material had been consumed [silica chromatography plates using methylene chloride/methanol (19:1) as the solvent]. The reaction mixture was then filtered and evaporated to give an oil which was "azeotroped" with toluene and triturated with ether. The decanted ether was evaporated to give the title compound as an oil, which was used directly without further purification, yield 0.45 g. ;<CDC13) : S 7.25 (d. 1H>; 6.95 (dd, 3H); 6.65 ;Odd, 1H); 6.6 (d, 2H); 3.85 (s, ;2H); 2.7 (s, 4H); 2.4 (s, 3H ). ;Preparations 2 to 4 ;The compounds of Preparations 2 and 3 were prepared similar to ;Preparation 1(C) by the reduction of the corresponding di-nitro compounds (see Preparations 6 and 5) using H2/Raney Ni/ethanol/3.5 kg/cm<2>/room temperature using reaction times of 4 and 17 hours respectively. The compound in Preparation 4 was prepared in the same manner as Preparation 1(C), but using H2/Pd/C in ethanol at 2/1 kg/cm<2> for 3 hours, the relevant dinitro starting material being subject to Preparation 8. ;Preparation 5 ;( A ) 4-( Isopropvlideneaminoxv )nitrobenzene ;;A solution of propanone oxime (30 g, 0.4 mol) in dry tetrahydrofuran (300 mL) was added slowly to a suspension of sodium hydride ( 10.8 g, 0.45 mol) in dry tetrahydrofuran (50 mL). After gas evolution was complete, dimethyl sulfoxide (100 mL) and 4-fluoronitrobenzene (57.85 g, 0.41 mol) were added and the reaction mixture was stirred at room temperature for 2 hours. 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 granulated in hexane and filtered, yield 67 g. A sample (7 g) was recrystallized from ethanol, yield 5 g, m.p. 104-106°C. ;Analysis ;Found: C 55, 6 ; H 5.05; N 14.35 Calculated for C9<H>10<N>2O3: C 55.7; H 5.2; N 14.4. ;( B) 2-methyl-5-nitrobenzofuran ;;4-(isopropylideneaminooxy)nitrobenzene (60 g, 0.309 mol) was added to glacial acetic acid (530 ml) containing gaseous hydrogen chloride (25 g) and the mixture was heated at 100° C for 18 hours. The solvent was evaporated and the residue "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, yield 46 g. A sample (5 g) was recrystallized from isopropanol, yield 2.5 g, m.p. 93-95°C. ;Analysis % : ;Found: C 61.2; H 4.1; N 7.9; ;Calculated for C9H7N03: C 61.0; H 4.0; N 7.9. ;( C) 2-bromomethyl-5-nitrobenzofuran ;;N-bromosuccinimide (1.1 g, 6.2 mmol) was added dropwise 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 at reflux for 6 h 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, yield 0.75 g, m.p. 96-98°C. ;Analysis ;Found: C 41.7; H 2.4; N 5.3; Calculated for C9H6BrN03: C 42.2; H 2.4; N 5.5. ;( D) N- methyl- N-(5- nitrobenzofur- 2-ylmethyl)- 4- nitrophenethylamine ;;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) were heated at reflux in acetonitrile (50 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 (MgSO 4 ) and evaporated to give a semi-solid, which was recrystallized from isopropanol to give the title compound, yield 380 mg. ;' H- N. m. r. (DMS0/TFA): = 8.75 (s, 1H); 8.3 (d, 1H); 8.2 ;(d, 2H); 7.9 (d, 1H); 7.6 (d, ; 2H); 7.45 (p, 1H); 4.75 (t, 2H); ;3.2 (t, 2H); 2.9 (p, 2H); 2.5 (p, ;3H). ;Preparation 6 ;fA) 2-bromomethyl-6-nitrobenzofuran ;;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 for 1 1/2 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 column chromatography on silica eluting with methylene chloride/hexane (7:3). The product-containing reactions were combined and evaporated to give the title compound, yield 1.43 g. <*>H-N.m.r. clearly showed that the product contained 20% 2-dibromomethyl-6-nitrobenzofuran, however, it was not considered necessary to remove this, and the product was used directly without further purification.

( B^ N- methyl- N-( 6- nitrobenzoxazol-2- ylmethyl)- 4- nitrophenethylamine

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 heated in acetonitrile at the reflux temperature for 18 h. The cooled reaction mixture was then filtered and the filtrate evaporated to dryness and purified by chromatography on silica eluting with methylene chloride/hexane (1:1) followed by methylene chloride/methanol (19:1). The product-containing fractions were combined and evaporated and the residue was treated with decolorizing charcoal in ethanol to give an oil which solidified on standing. Recrystallization from the solid from ethanol/methylene chloride gave the title compound, yield 0.27 g, m.p. 69-69.5°C.

Analysis % :

Found: C 60.8; H 4.8; N 11.8; Calculated for C^gH^^O^: C 60.8; H 4.8; N 11.8.

'H-n.m.r. (CDCl 3 ): S 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 (p, 2H);

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

(p, 3H).

Manufacturing 7

(A) 2-hydroxymethyl-3-methyl-5-nitrobenzofuran

1 molar diborane in tetrahydrofuran (18.0 mL, 18.0 mmol) was added dropwise to a suspension of 3-methyl-5-nitrobenzofuran-2-carboxylic acid (1.1 g, 5 mmol) in tetrahydrofuran at 0°C. Stirring was continued at 0°C for 30 minutes, then at room temperature for 18 hours after which a second portion of diborane (5.0 mL) was added and the reaction mixture was sonicated for 2.5 hours. Methanol was then 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, dried (MgSO 4 ), the solvent removed by evaporation in vacuo and purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and evaporated to give the title compound, yield 0.96 g. A sample was recrystallized from ethyl acetate, m.p. 149-150°C.

Analysis % :

Found: C 57.9; H 4.2; N 6.7; Calculated for C10H9NO4: c 58.0; H 4.4; N 6.8. (B) 2-chloromethyl-3-methyl-5-nitrobenzofuran

Thionyl chloride (1.48 g, 12.4 mmol) was added dropwise 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 separated, and the aqueous phase re-extracted with methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate, dried (Na 2 SO 4 ) and the solvent evaporated to leave the title compound, 0.93 g. A portion was recrystallized from ethanol, m.p. 141-142°C.

Analysis % :

Found: C 52.95; H 3.7; N 6.0; Calculated for C10<H>8C1N03: C 53.2; H 3.6; N 6.2.

Manufacturing 8

N-methyl-N-(6-nitroquinol-2-methyl)-4-nitrophenethylamine

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

Analysis % :

Found: C 62.4; H 4.7; N 15.2; Calculated for C19<H>18N4O4: C 62.3; H 4.95; N 15.3.

'H-n.m.r. (CDCl 3 ): = 8.9 (d, 1H); 8.5 (dd, 1H);

8.3-8.1 (m, 3H); 7.6 (d, 1H);

7.35 (d, 1H); 3.95 (p, 2H); 3.0

(t, 2H); 2.8 (t, 2H); 2.4 (pp,

3H).

Production 9

(A) 4- methanesulfonamidophenethyl mesylate

Methanesulfonyl chloride (146.6 g, 1.28 mol) was added dropwise 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 to give the title compound, yield 31 g, m.p. 134-136'C. A further 14.5 g of product was obtained by concentration of the mother liquors in vacuo.

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

4-Methanesulfonamidophenethyl mesylate (10 g, 34 mmol) and N-ethylbenzylamine (10 mL, 67 mmol) were heated at reflux in ethanol (80 mL) for 3 h. The solvent was evaporated, the residue taken up in 2M hydrochloric acid and washed twice with methylene chloride. The aqueous layers were acidified with sodium bicarbonate (to pH 12) and extracted with methylene chloride. The latter organic extract was dried (MgSO 4 ) and evaporated to give an oil which solidified by trituration with diisopropyl ether. The solid was filtered off and discarded and the filtrate evaporated in vacuo to give the title compound as an oil, yield 4.4 g. 7.05 (s, 4H); 3.6 (s, 2H); 2.95 (s, 3H); 2.70 (s, 4H); 2.40 (q, 2H); 1.1 (t, 3H) . (C) N-ethyl-4-methanesulfonamidophenethylamine

N-Benzyl-N-ethyl-4-methanesulfonamidophenethylamine (4.3 g, 12.9 mmol) was stirred under a hydrogen atmosphere (3.5 kg/cm<2>) in ethanol (50 mL) containing 10% Pd/ C (0.5 g) for 5 hours. The mixture was then filtered, evaporated and the residue triturated with ether to give the title compound, yield 2.6 g, m.p. 125-128°C.

N. m. r. (CDCl 3 /DMSO): S = 7.06 (s, 4H); 4.9 (p, 2H); 2.86

(s, 2H); 2.8 (p, 2H); 2.65 (q,

2H); 1.05 (t, 3H).

Production 10

(A) N- methyl- N-(3- methyl- 5- nitrobenzofur- 2- methyl)- 4-methanesulfonamidophenethylamine

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 at reflux in ethanol (20 ml) for 3 hours. The solvent was then evaporated and the residue was purified by column chromatography on silica eluting with methylene chloride/hexane (4:1) followed by methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated, and the residue was recrystallized from ethanol to give the title compound, yield 1.52 g, m.p. 124-124.5'C.

Analysis

Found: C 57.7; H 5.65; N 10.0; Calculated for C20<H>23<N>3O5S: C 57.5; H 5.55; N 10.1.

H- n. m. r. (CDCl 3 ): = 8.45 (d, 1H); 8.25 (dd, 1H); 7.5

(d, 1H); 7.2 (q, 4H); 3.8 (pp,

2H); 3.05 (p, 3H); 2.9 (t, 2H);

2.75 (t, 2H); 2.4 (p, 3H); 2.35

(p, 3H).

(B) N- methyl- N-(3-methyl-5- aminobenzofur-2-ylmethyl)-4-methanesulfonamidophenethylamine

Catalytic hydrogenation of the product from part (A) (0.7 g) similar to Preparation 1(C) with a reaction time of 4 hours gave the title compound (0.65 g).

' H- N. m. r. (CD30D): = 7.25 (m, 6H); 6.9 (d, 1H); 6.8

(dd, 1H); 3.8 (p, 2H); 2.95 (pp,

3H); 2.9 (m, 2H); 2.7 (m, 2H);

2.4 (p, 3H); 2.35 (p, 3H).

Produce incr 11

( A) N- ethyl- N-( 6- nitroquinol- 2- ylmethyl)- 4- methane- sulfonamido- pheneth<y>lamine

N-ethyl-4-methanesulfonamidophenethylamine (see Preparation 9(C)

- 1:7 g, 7.0 mmol) and 2-chloromethyl-6-nitroquinoline (0.78 g, 4.1 mmol) were heated at reflux in ethanol (50 mL) for 4 h. The solvent was then evaporated and the residue was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried (MgSO 4 ), evaporated and the residue was purified by column chromatography eluting with methylene chloride. The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.56 g.

'H-N.m.r. (CDCl 3 ): g = 8.6 (d, 1H); 8.3-8.0 (m, 2H); 7.6

(d, 1H); 7.1 (p, 1H); 7.0 (s,

4H); 3.9 (p, 2H); 2.9 (p, 2H);

2.7 (p, 2H); 2.65 (q, 2H); 1.05

(t, 3H).

(B) N-ethyl-N-(6-aminoquinol-2-ylmethyl)-4-methanesulfonamidophenethylamine

The product from part (A) (0.55 g) was catalytically hydrogenated in the same manner as in Preparation 1(C), but using H 2 over 5% Pd on C in ethyl acetate at 1.05 kg/cm<2> in 3 h, which gave the title compound (0.51 g).

' H- N. m. r. (cDClg): 8 = 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 (pp,

3H); 2.6 (p, 4H); 2.5 (q, 2H);

0.95 (t, 3H).

Production 12

(A) 6-amino-2-methylquinoline

2-Methyl-6-nitroquinoline (18.8 g) was stirred under a hydrogen atmosphere at 2.1 kg/cm<2> (equal to 206.8 kPa) for 2 hours in ethanol solution containing 5% Pd/C. The catalyst was then removed by filtration, the filtrate evaporated to a small volume in vacuo, and the resulting precipitate collected by filtration, washed with ethanol and ether and dried to give the title compound, yield 13.2 g, m.p. 188-189"C.

Analysis

Found: C 75.7; H 6.4; N 17.6;

Calculated for C10<H>10<9>N2: C 75.9; H 6.4; N 17.7.

(B) 6-methanesulfonamido-2-methylquinoline

Methanesulfonyl chloride (6.2 mL) was added dropwise to a stirred solution of 6-amino-2-methylquinoline (12.5 g) in pyridine (100 mL) cooled to 5°C. Stirring was continued for 17 hours at room temperature. The pyridine was then removed by evaporation in vacuo, the residue diluted with aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were combined, dried (MgSO 4 ) and evaporated in vacuo to give the title compound, yield 13.0 g, m.p. 151-153°C.

Analysis

Found: C 55.4; H 5.2; N 11.6; Calculated for C11<H>12<N>2°2S: c 55.9; H 5.1; N 11.9.

(C) 6-methanesulfonamido-2-methylquinoline-1-oxvd

m-chloroperbenzoic acid ("MCPBA") (5.2 g) was added portionwise 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 aq

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 (MgSO 4 ) and evaporated in vacuo to give a solid which was recrystallized from ethanol to give the title compound, yield 1.6 g, m.p. 241-243°C.

Analysis

Found: C 52.5; H 4.95; N 11.0; Calculated for C11<H>12<N>2°3S: C 52.4; H 4.8; N 11.1.

(Dl 2-chloromethyl-6-methanesulfonamidoquinoline

6-methanesulfonamido-2-methylquinoline-1-oxide (1.65 g) and p-toluenesulfonyl chloride (1.72 g) were heated under reflux for 1 hour in 1,2-dichloroethane solution, and the reaction mixture was then allowed to stand at room temperature for 17 hours. The reaction mixture was then washed twice with aqueous sodium bicarbonate, dried (MgSO 4 ) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methanol containing methylene chloride (0% up to 1%). The product-containing fractions were combined and evaporated to give a gum which solidified when triturated with ether. Recrystallization from toluene gave the title compound, yield 0.75 g, m.p. 160-162°C.

Analysis % :

Found: C 49.3; H 3.9; N 10.1; Calculated for C11<H>11<N>202C1S: C 48.8; H 4.1; N 10.35.

Production 13

(A) 2-chloromethyl-5-nitrobenzo rblthiophene

Thionyl chloride (1.0 mL) was added dropwise to a stirred mixture of 5-nitrobenzo[b]thiophene-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 washed with water followed by aqueous sodium bicarbonate solution, and then dried (Na2SO4). 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), m.p. 110-112°C, used directly in the next step.

(B) N- methyl- N- f 5- nitro- 2- benzo rb] thienylmethy11- 4- nitrophenethylamine

A mixture of the product from part (A) above (3.20 g), 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 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 first gave impurity followed by pure product. The product-containing fractions were evaporated to give the title compound (4.17 g), m.p. 76-78°C.

Analysis % :

Found: C 57.8; H 4.4; N 11.1; Calculated for C18<H>17<N>304S: C 58.2; H 4.6; N 11.3.

(C) N- roetvl- N- r5- amino- 2- benzo[ bltienylmetvlT- 4- aminophen-ethylamine

A mixture of the product from (B) above (1.0 g) and stannous (II) chloride dihydrate (6.07 g) in ethanol (100 ml) was heated under reflux for 8 hours and then evaporated. An excess of 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 (Na 2 SO 4 ) and evaporated to give an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol (99:1) gave impurity and then further elution with dichloromethane/methanol (98:2) after collection and evaporation of appropriate fractions gave the product as an oil (0.30 g) which was used immediately in the process in example 6.

Production 14

(A) 4-f 2-(methanesulfonyloxy)ethyl]-methanesulfonanilide

Methanesulfonyl chloride (50 mL) was added dropwise over 1/2 hour to a stirred 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. The mixture was then poured onto water (700 mL), from which an orange colored solid crystallized. After filtration, the solid was dissolved in methylene chloride, dried over magnesium sulfate, filtered and the filtrate re-evaporated. Crystallization of the resulting solid from ethyl acetate gave the title compound, 45.5 g, m.p. 136-137°C.

Analysis % :

Found: C 40.6; H 5.2; N 4.9; Calculated for C10<H>15N05S2: C 40.9; H 5.15; N 4.8.

(B) 4-r 2-(methylamino)ethyl]methanesulfonanilide

To a solution of 4-[2-(methanesulfonyloxy)ethyl]methanesulfonanilide (10.3 g) in ethanol (20 ml) was added a solution of methylamine in methanol denatured alcohol (30 ml of a 33% solution). The mixture was heated with stirring at 85°C in a pressure vessel for 17 hours. After cooling, the resulting solution was acidified by the addition of sodium hydroxide (1.4 g) in water (12 ml). Evaporation gave an off-white solid which was chromatographed on silica ("Kieselgel 60") eluting with methylene chloride/methanol (3:1). Collection and evaporation of appropriate fractions gave an off-white solid (4.8 g) which crystallized from ethyl acetate/methanol to give the title compound, 1.8 g, m.p. 133-135°C.

Analysis % ;

Found: C 52.5; H 7.1; N 12.2; Calculated for C10<H>16N2O2S: C 52.6; H 7.1; N 12.3.

Claims (2)

) or a pharmaceutically acceptable salt thereof, wherein R<1> is C-| -C4 alkyl and "Het" is a group with the formula: or where R<2> is H or CH3, and X is 0 or S characterized by either (A) acylating a compound of formula: where Ra is -NH2 or -NHSO2(<C>1-C4 alkyl), R<1> is C-^-C^ alkyl, and "Het" is a group of the formula: where R<2> and X are as defined above, and R<b> is -NH2 or -NHS02 (C2-C4 alkyl) with the proviso that Ra and R<b> are not both -NHS02 (C^C^) alkyl; with a C 1 -C 4 alkanesulfonyl chloride or bromide or a C 1 -C 4 alkanesulfonyl anhydride; or (B) react a compound with the formula: with a connection with the formula wherein one of R<c> and Rd is -NHR<1> and other is a leaving group, and R<1> and "Het" are as defined above; said methods (A) and (B) being optionally followed by conversion of the product of formula (I) into a pharmaceutically acceptable salt. 2. Method according to claim 1 (A) in the preparation of a compound with formula: characterized by reaction of N-methyl-N-(5-aminobenzofur-2-ylmethyl)-4-aminophenethylamine with methanesulfonyl chloride in the presence of an acid acceptor.